• Open Access
    Review

    The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

    Maria Teresa Palano 1
    Matteo Gallazzi 2
    Martina Cucchiara 2
    Federico Dehò 3
    Paolo Capogrosso 3
    Antonino Bruno 1,2†*
    Lorenzo Mortara 2†*

    Explor Target Antitumor Ther. 2022;3:694–718 DOI: https://doi.org/10.37349/etat.2022.00108

    Received: June 29, 2022 Accepted: August 12, 2022 Published: October 31, 2022

    Academic Editor: Fathia Mami-Chouaib, Université Paris-Saclay, France

    This article belongs to the special issue Cancer Immunotherapy and Tumor Microenvironment

    Abstract

    Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME.

    Keywords

    prostate cancer, tumor immune microenvironment, innate immune cell polarization, cytokines

    Introduction

    Prostate cancer (PCa), the most common non-cutaneous disease affecting the male population, still accounts as the first cancer for incidence in males. Metastasis still represents a major challenge for PCa patient’s survival: while patients with primary tumor are characterized by a 5-year survival of 99%, only the 22% of subjects with metastatic disease, whose bone accounts as the primary site for dissemination, experienced a 5-year survival [1, 2]. As multifocal pathology, PCa is characterized by large intratumor heterogeneity [3], a relevant hallmark that strongly impact both on the surrounding tumor microenvironment (TME), tumor immune microenvironment (TIME) and response to therapy [3, 4].

    With the introduction of the concept of immunoscore [5, 6], PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells [such as myeloid-derived suppressor cells (MDSCs), type-2 macrophage (M2)-like/tumor-associated macrophages (TAMs), T regulatory (Treg) cells], favoring the infiltration/activation of anti-tumor immune cells (such as natural killer (NK) cells, CD8+ T cells) [7, 8]. This concept clearly places the TIME as a crucial element of PCa, that still requires a deep characterization, to define therapies able in targeting the PCa-TIME.

    Here, we reviewed and discussed selected major soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of progression, immunosuppression, and angiogenesis within the PCa-TIME.

    Selected soluble factors in TIME in PCa

    The TME is enriched of soluble factors [9], produced both by tumor cells, stromal [10] and immune-infiltrating cells [1114] that strongly impact of the extremely heterogeneous cellular phenotypes and functions found in the TIME. These soluble factors are also relevant in regulating the aberrant/altered cell-to-cell and cell-to-extracellular matrix (ECM) interactions within the TME, regulating key process in tumorigenesis, such as tumor cell proliferation, angiogenesis, and immunosuppression, thus impacting on response to therapies.

    TGFβ

    TGFβ a ubiquitously expressed cytokine, is directly involved in several pathophysiological processes both in development and adult life, ranging to tissue healing/repair, fibrosis, and cancers [15, 16]. TGFβ accounts as a master regulator in response to tissue injury inducing epithelial-to-mesenchymal transition (EMT), fibroblast activation, cell migration, and modulates immune response [17]. TGFβ promotes cell cycle arrest, apoptosis and differentiation, thus regulating the overall cell homeostasis [17]. TGFβ dysregulation has been found as a shared features in diverse cancers [18, 19], where it exerts different roles, as related to cancer stages [2022]. At early stages, TGFβ suppresses tumor growth, acting as a tumor suppressor gene, while during latest stages and in metastasis TGFβ enhances tumor growth and promotes angiogenesis, migration, and invasion [23].

    The TGFβ target gene, peroxisome proliferator activated receptor delta (PPARδ) seems to play a crucial role in regulating TGFβ paradox in PCa, thus PPARδ repression increases the inhibitory effect of TGFβ on tumor cells, while PPARδ induction promotes TGFβ pro-tumoral functions (Figure 1A) [24]. In PCa cells, unresponsiveness to the TGFβ antiproliferative function [25] maybe due to the lack of TGFβ-receptor expression and correlates with high grade tumors [26].

    Within TME, TGFβ is expressed and produced by different cell types, including tumor cells, tumor stroma, and infiltrating immune cells [23]. TGFβ acts as one of the most immunosuppressive factors in the TIME, further supporting tumor progression (Figure 1A). Immunosuppressive activities of TGFβ include inhibition of cell cytotoxicity induction of Treg cell development and differentiation, by inducing forkhead box p3 (Foxp3) expression, a specific marker of Treg subset that controls and maintains immune tolerance and homeostasis (Figure 1A) [27, 28]. Also, TGFβ induce the suppression of CD8+ T cell activity and support PCa growth and immunoescape [29]. TGFβ has been reported to support therapy hormonal resistance in PCa; of note, TGFβ blockade has been found to limit this effect, by inducing apoptosis in tumor cells, limiting angiogenesis and improving immune cell infiltration and anti-tumor immunity in PCa [30].

    Mechanisms that involved soluble factors in PCa. A) TGFβ: PPARδ, a TGFβ target gene, play a crucial role in regulating TGFβ paradox in cancer (from oncosuppressor to a tumor-promoting factor); PPARδ repression increases the inhibitory effect of TGFβ on tumor cell while PPARδ induction promotes TGFβ pro-tumoral functions; one of the crucial roles of TGFβ in orchestrating TME is mainly focused on immune cells on which works as immune suppressor molecule thus sustaining immune pro-tumoral functions; TGFβ is involved in Treg cell development and differentiation by inducing Foxp3 expression, a specific marker of Treg subset that controls and maintains immune tolerance and homeostasis. B) IL-6: IL-6 mediated activation of signal transducer and activator of transcription (STAT)/Janus kinase (JAK) axis has been demonstrated to support PCa cell proliferation, via extracellular signal-regulated kinase 1 and 2 (ERK1/2)-mitogen activated protein kinase (MAPK) pathway, and the phosphoinositide 3-kinase (PI3-K) pathway; IL-6 play a major role in increasing PCa aggressiveness by instructing EMT and homing of metastatic clones to the bone; IL-6 receptor (IL-6R) signaling has been demonstrated to be crucial in favoring the neuroendocrine differentiation in PCa, by the canonical activation of STAT3 transcription factor. C) IL-10: IL-10 is expressed by several cell types of the immune system, including dendritic cells (DCs), NK cells [2729], eosinophils, neutrophils, and T cell subsets. IL-10 also induces expression of neuroendocrine markers and programmed death-ligand 1 (PD-L1) in PCa cells. D) IL-23: IL-23 mediate expansion of Th17 cells and acts as a prognostic factor in patients with metastatic PCa; other mechanisms involving IL-23 as regulator of metastatic PCa, include the altered stimulation of the retinoic acid receptor-related orphan receptor gamma (RORγ) and STAT3 pathways; IL-23, produced by MDSCs, serve as promoter of castration-resistant prostate cancer (CRPC), by activating androgen receptor (AR) signaling and enhancing cell proliferation in a non-cell autonomous manner in PCa. prolif: proliferation; Th2: T helper 2; red arrows up and down: upregulation/increase and downregulation/decrease

    TGFβ has been reported to synergize with IL-6, IL-7, C-X-C motif chemokine ligand 8 (CXCL8)/IL-8 in promoting the EMT process, which is an essential phenomenon in metastasis formation [3134]. TGFβ can support EMT and metastasis development, via AR. The silencing of AR in transgenic adenocarcinoma of the mouse prostate (TRAMP) animals, has been reported to support EMT, by reducing Epithelial-cadherin (E-cadherin) expression and increasing vimentin and Neural-cadherin (N-cadherin) expression [35]. AR knock-down increases cell migration and metastasis formation, in a TGFβ dependent manner [35]. On the other way, TGFβ suppression could lead to the up-regulation of ERK which could stimulate EMT-dependent migration and invasion of PCa cells [36].

    Increased level of circulating TGFβ is associated with a worse prognosis in PCa patients [37]. Within prostate tissue, high expression of TGFβ is linked to poor prognosis while lower expression is associated with benign tumors [38].

    The role of TGFβ in PCa growth and progression exerts a complex and wide action on both tumor cells and microenvironment suggesting the use of this molecule as positive (with enhancing therapy) and negative (inhibition) regulator of TME depending on/according to the tumor stages and landscape.

    IL-6

    IL-6 is a pleiotropic pro-inflammatory cytokine largely expressed in PCa. IL-6 can be expressed both by the tumor, stromal and immune compartments in PCa [3941]. Major effects of IL-6 include its abilities to regulate cell proliferation, cell differentiation, apoptosis, inflammation, and angiogenesis [3941]. As established major soluble mediator of inflammation, IL-6 is crucial in governing cancer-related inflammation, including in PCa [41, 42].

    IL-6 account as a major activator of the signaling pathway of JAK and STAT3, thus acting as a master regulator within the PCa TME [39, 43, 44]. IL-6 mediated activation of JAK/STAT axis has been demonstrated to support PCa cell proliferation, via ERK1/2-MAPK pathway, and the PI3-K pathway (Figure 1B) [45]. IL-6 has been found to synergize with oncostatin-M (OSM) in promoting PCa aggressiveness and malignancy via PI3K/AKT pathway in vivo and in PCa human tissues [45].

    Also, IL-6 play a major role in increasing PCa aggressiveness by instructing EMT and homing of metastatic clones to the bone (Figure 1B). Also, aggressiveness and recurrence of PCa has reported to correlate with IL-6 polymorphisms [46]. Elevated serum levels of IL-6 have been detected in patients with untreated metastatic or CRPC, thus negatively correlating with tumor survival and response to chemotherapy. IL-6 is also implicated in the transition from hormone-dependent to CRPC, by transactivation of the AR.

    In a study performed on 74 PCa patients, Nakashima et al. [47] found that serum IL-6 significantly correlated with the clinical stage of PCa, as recently confirmed by Zhou et al. [48] in a study showing that plasma IL-6 and TNFα levels significantly correlate with grading changes in localized PCa. IL-6R signaling has been demonstrated to be crucial in favoring the neuroendocrine differentiation in PCa, by the canonical activation of STAT3 transcription factor (Figure 1B) [49].

    IL-10

    IL-10 is a cytokine characterized by its pleiotropic effects in immunoregulation and inflammation [5052]. IL-10 has a central role during infection, by limiting the immune response to pathogens and thereby preventing damage to the host [53]. IL-10 was initially described as Th2-type cytokine [54]; further studies clearly demonstrated production of IL-10 was associated with tolerant or Treg cell responses. It is now well consolidated that IL-10 is expressed by many cells of the immune system, including DCs [5557], NK cells [5860], eosinophils [61, 62], neutrophils [63, 64], and all the T cell subsets (Th1, Th2, Th17, Treg, CD8+ T cells) (Figure 1C) [6569]. By its anti-inflammatory and immunosuppressive activities, IL-10 support tumor progression, limiting efficient anti-tumor response [7072].

    IL-10 has been detected as elevated serum samples of PCa patients and has been correlated with poor prognosis and positively correlated with Gleason score [73]. Also, IL-10 and heat shock protein 90 (HSP90) expression revealed a highly significant correlation in advanced Gleason grading and tumor, node, and metastasis (TNM) staging cases of PCa [73]. A meta-analysis performed by Shao et al. [74] investigated the relation with IL-10 polymorphism and PCa, based on the fact that three common polymorphisms in the promoter of IL-10 gene, −1082 A > G, −819 C > T, and −592 C > A, have been implicated to alter the risk of PCa [74] that have been considered as a controversial issue. The authors concluded that IL-10 −1082 A > G, −819 C > T, and −592 C > A polymorphisms show significant evidence to be associated with PCa risk [74]. Therefore, L-patients carrying the IL-10 −819 C > T and −592 C > A might develop a highly aggressive PCa [74].

    Finally, Samiea et al. [75] recently demonstrated that IL-10 induces expression of neuroendocrine markers and PD-L1 in PCa cells, by supporting tumor cell survival by interaction with PD-1, and favoring immunosuppression (Figure 1C).

    IL-23

    IL-23 is a heterodimeric cytokine consisting of two subunits, IL-12B and IL-23A, that belongs to the IL-12 group of cytokines. It is now largely demonstrated that the balance between the proinflammatory cytokine IL-12 and IL-23 in tumors is crucial in shaping the development of anti-tumor or pro-tumor immunity [76]. IL-23 was found to be overexpressed in many human tumors, including lung [7779], colorectal [8082], breast [83], ovarian [84], pancreatic [85], prostate [86], bladder [87] cancers, and multiple myeloma [88].

    IL-23 has been reported to repress the level of cell senescence, induced by the AR antagonist enzalutamide and darolutamide, in CRPC cells [89]. Calcinotto et al. [86] found that MDSCs and IL-23 concentration increase in peripheral blood and tumor tissues from patients with CRPC. The authors also demonstrated that IL-23, produced by MDSCs, serves as promoter of CRPC, by activating AR signaling and enhancing cell proliferation in a non-cell autonomous manner in PCa (Figure 1D) [86]. Treatments able in blocking IL-23 were effective in contrasting MDSC-mediated resistance to castration and synergize with standard therapies in PCa [86]. Other mechanisms involving IL-23 as regulator of metastatic PCa, include the altered stimulation of the RORγ and STAT3 pathways (Figure 1D). Liu et al. [90] reported that IL-23 mediate expansion of Th17 cells and acts as a prognostic factor in patients with metastatic PCa (Figure 1D). Also, IL-23+ cells have been found to increase in PCa tissues and correlates with disease progression, as confirmed by The Cancer Genome Atlas (TCGA)-prostate adenocarcinoma (PRAD) cohort analysis [90]. TCGA-PRAD analysis also revealed that IL-23 expression associates with poor survival and CRPC-free survival. Increased presence of IL-23+ cells has been reported in PCa metastatic lesions as compared to non-metastasized ones [90]. Concerning the PCa therapeutic treatments, authors found that IL-23+ cells can predict poor clinical outcomes in patients receiving the abiraterone treatment, while no similar effect was observed in patients undergoing docetaxel treatment [90].

    Tumor innate immune microenvironment in PCa

    The TME is characterized by extreme heterogeneity in cellular composition, that includes tumor cells and diverse cells of the host, such as cancer associated fibroblasts (CAFs), normal fibroblasts (NFs), endothelial cells (ECs) of the new generated blood vessels, and cells of both innate and adaptive immune system [91]. Here we focused our attention on the activities of selected innate immune cells found in the PCa tumor innate immune microenvironment (TIIME).

    Mast cells

    Mast cells (MCs) are innate immunity effector cells primarily involved in the inflammatory response and allergy [92, 93]. The identification of tumor-infiltrating MCs dates to late 19th century [92, 93]. Studies examining both human cancer tissues as well as using experimental models show that MCs can exert either anti-tumor or pro-tumor activities. This dual role is strictly regulated by the tumor type, MC interactions with microenvironmental signals and with neighboring cells [85]. Apart for their “canonical role”, MCs have been reported to be able to produce several factors that can support tumor growth, such as CXCL8/IL-8, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), stem-cell factor (SCF), together with matrix metalloproteases (MMPs), necessary for the ECM remodeling, thus favoring metastasis [9496].

    MC-mediated anti-tumor activities relate to their ability to produce IL-1, IL-6, TNFα that induce apoptosis in tumor cells, together with chondroitin sulfate, that could exert a decoy activity by inhibiting metastases [97]. This dual behavior by MCs has also been observed in PCa, depending on tumor staging. While in early phase tumors MCs acquire pro-tumorigenic properties, they became protective in late-stage cancer, particularly in the case of the highly aggressive neuroendocrine PCa (Figure 2A). In PCa, MCs have been found to be enriched in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated foci coexisting in the same tumors [98]. Of notice, while MCs exert pro-tumor activities in WD adenocarcinomas, by producing MMP-9 [96] and suppressing CD8+ T cell response [96] (Figure 2B), via crosstalk with polymorphonuclear (PMN)-MDSCs, MCs have been found to acquire protective functions by interfering with de novo generation of neuroendocrine tumors [94, 96, 97] (Figure 2C).

    TIIME in PCa. MCs: A) The Janus behavior by MCs (production of IL-1, IL-6, and TNFα) depends on tumor staging: in early phase tumors, MCs acquire pro-tumorigenic properties; they became protective in late-stage cancer. B) MCs exert pro-tumor activities by producing MMP-9 and suppressing CD8+ T cell response. C) MCs have been found to acquire protective functions, via crosstalk with PMN-MDSCs, by interfering with de novo generation of neuroendocrine tumors. MDSCs: D) Brusa et al. [99] showed that circulating monocytes-MDSCs (M-MDSCs) increase in frequency, before and following radical prostatectomy, whereas Hossain et al. [100] showed higher frequency of blood PMN-MDSCs in PCa patients. E) Targeting Toll-like receptor 9 (TLR9)+ PMN-MDSCs, by STAT3 silencing, with cytosine-phosphate-guanine (CpG)-STAT3 small interfering RNA (siRNA) conjugate, Hossain et al. [100] found that this approach is successful on blocking the immunosuppressive activity in vitro of MDSCs on CD8+ T cells of PCa patients. Neutrophils: F) Neutrophils within the PCa TME, expressed IL-6R and the high amount of IL-6 in TME induces STAT3 mediated activation of immunosuppressive features. G) An in vitro study showed that neutrophil elastase (NE), a serine protease stored in neutrophils, induces ERK signaling in a dose dependent manner and activation of the AXL receptor tyrosine kinase (AXL) in PCa cell lines which showed increased migratory capability. H) Tumor-associated neutrophils (TANs) can also influence angiogenesis within TME of PCa and metastasis. NK cells: I) PCa tumor infiltrating NK are characterized by reduced expression of the activation receptor NK Group 2D (NKG2D), together with impaired degranulation capabilities and reduced production and release of cytolytic molecules, such as perforin, granzymes, and interferon gamma (IFNγ). J) Tumor infiltrating NK cells in PCa patients are enriched in immature CD56bright cells. K) PCa cancer cells support the expression of Ig-like transcript 2 (ILT2)/leukocyte immunoglobulin like receptor B (LILRB) inhibitory receptors, together with downregulation of NKG2D and NKp46 and CD16 on NK cells. L) PCa circulating NK cells were found to increase their expression of PD-1 and T-cell immunoglobulin mucin family member 3 (TIM-3; as cell exhaustion markers), together with decreased level of NKG2D and degranulation capabilities, compared to circulating NK cells from control subjects. M) M2-like/TAMs in tumor environment limit NK cells cytotoxicity against metastatic CRPC (mCRPC) cells, by enhancing the PD-L1 levels and reducing NKG2D ligands production, through the IL-6-STAT3 pathway. N) IL-6, another abundant cytokine present both at tissue and systemic levels in PCa patients, limit NK cell anti-tumor activities, via STAT3 activation, by decreasing major histocompatibility complex-class I chain related proteins A and B (MICA/B) and UL16 binding proteins (ULBPs) NK cell-activating ligands, resulting in decrease NK cell killing capabilities. STAT3 activation in NK cells also results in reduced expression of activating receptors NKG2D, DNAX accessory molecule-1 (DNAM-1), IFNγ, and TNFα secretion. STAT3 was found to activate the rapidly accelerated fibrosarcoma (Raf)-mitogen-activated ERK kinase (MEK)-ERK-activator protein-1 (AP-1) pathway, which directly induces the expression of the T cell immunoreceptor with Ig and ITIM domains (TIGIT), in NK cells. O) NK cells isolated from peripheral blood of PCa patients acquire the CD56brightCD9+CD49a+(C-X-C motif chemokine receptor 4) CXCR4+ decidual-like phenotype and exhibit pro-angiogenic functions, inducing tube formation by endothelial cells, due to increased production of VEGF, CXCL8, CXCL12 and M2-like/TAM polarization. Monocytes/Macrophages: P) The M2-like TAM phenotype is driven by different stimuli within TME which include C-C motif chemokine ligand 2 (CCL2), colony stimulating factor 1 (CSF-1) as well as granulocyte-macrophage CSF (GM-CSF) and TGFβ, produced by cancer and stromal cells, that strongly contribute to macrophages polarization and in the generation of an immunosuppressive environment, via CXCL12 and IL-6. Q) Cancer cell/macrophage crosstalk is also driven to the opposite direction, as TAMs promote cancer progression, by stimulating migration and invasion, trough CCL22-C-C motif chemokine receptor 4 (CCR4) axis activation. R) TAM-derived CCL5 activates STAT3 signaling in cancer cells and increases cell migration, EMT, and cell invasion, as well as supports cancer stem cell self-renewal. Red arrows up and down: upregulation/increase and downregulation/decrease

    In a study performed using the H-subline of the Dunning tumor (Dunning-H) and angiotensin II type-1 (AT-1) models of PCa, Johansson et al. [101] found that intra-tumoral and peri-tumoral MCs have completely different behavior. In this study, while intertumoral MCs negatively regulate angiogenesis and tumor growth, peritumoral MCs were found to support PCa expansion. Moving to the human setting, the authors observed that patients with increased frequency of MCs in in the non-malignant stroma associated with poor prognosis in a significantly statistic manner [101]. Finally, the authors found that castration therapy increase MCs recruitment [101].

    MDSCs

    MDSCs represent a heterogeneous immature myeloid cell population endowed with immunoregulatory functions and in particular inhibitory features against CD8+ cytotoxic T cells and NK cells in the TME of different types of cancers [102, 103]. Moreover, MDSCs are also involved in tumor angiogenesis and metastasis [104]. MDSCs were originally identified, in mice, as immature myeloid cells co-expressing granulocyte antigen type 1 (Gr-1) and CD11b surface markers [102]. Subsequently, murine MDSCs were characterized as two distinct subpopulations based on differences in their morphology and surface marker expression: cells resembling to granulocytic PMN cells, termed PMN-MDSCs, and cells with features shared with monocytes, named M-MDSCs. In mice, PMN-MDSCs are defined as CD11b+ lymphocyte antigen 6 complex locus C (Ly6C)low lymphocyte antigen 6 complex locus G (Ly6G)+ cells, whereas M-MDSCs as CD11b+Ly6ChighLy6G. In humans PMN-MDSCs are identified as CD11b+CD14−CD15+ cells or CD11b+CD14−CD66b+ cells, and M-MDSCs as CD11b+CD14+ major histocompatibility complex, class II, DR (HLA-DR)−/lowCD15 cells [104]. Mechanisms involved in MDSCs-dependent immune regulation are multiple and include depletion of arginine by arginase-1 (ARG1), release of nitric oxide (NO) by the inducible NO synthase (iNOS), and production of reactive oxygen species (ROS). Moreover, these cells exert indoleamine 2,3-dioxygenase (IDO) enzyme activity causing tryptophan elimination and induction of kynurenine inhibitory metabolite and activation of Treg cells by IL-10 and TGFβ production [105107].

    Patients with PCa have increased circulating and tumor infiltrating MDSCs. Brusa et al. [99] showed that circulating M-MDSCs were augmented before and following radical prostatectomy, whereas Hossain et al. [100] reported increased frequency of circulating PMN-MDSCs in PCa patients (Figure 2D), compared to healthy subjects, and this increase turned out to be more than double in the mCRPC patients. Moreover, Idorn et al. [108] found that circulating M-MDSCs increase in patients with CRPC, together with increased number of Treg cells, correlating with negative prognosis and with a shorter median overall survival (OS). High numbers of intratumor MDSCs have been also reported in patients, that do not respond to androgen deprivation therapy [86].

    Given the close dependence of these cells on STAT3 signaling, Hossain et al. [100] generated a CpG-STAT3 siRNA conjugate that, by targeting TLR9+ PMN-MDSCs limits the immunosuppressive activity of MDSCs on CD8+ T cells of PCa patients, in vitro (Figure 2E). At the same time, in different mouse models of PCa it has been demonstrated the role of CD11b+Gr-1+ MDSCs in tumor initiation and progression [99]. As also showed by Calcinotto et al. [86] in several murine models of PCa, including the phosphatase and tensin homolog (PTEN) conditional knockout (KO) and TRAMP-C1 mouse models, PMN-MDSCs can activate the AR pathway by IL-23 release and favor tumor cell proliferation even after androgen inhibition. Antibody-mediated blockade of IL-23 or IL-23 receptor can counteract MDSCs’ effects on resistance to castration and restore androgen deprivation therapy. The interplay between IL-23 and MDSCs is in line with observation in humans, since CRPC patients showed both elevated levels of IL-23 and increased number of MDSCs in blood and tumor [86]. It has been also shown that PCa-derived CXCL5 can recruit CXCR2-expressing MDSCs in a mouse model of PCa and inhibition of MDSCs through blocking of CXCL5-CXCR2 axis can restore anti-tumor activities [109].

    Therefore, given the implications and involvement of MDCSs in PCa pathology, these cells have become central to the study of new therapeutic approaches for PCa and/or CRPC [110].

    Neutrophils

    Neutrophils are professional phagocytes of the innate immunity, are primarily involved in early host defense form pathogens and induction of acute inflammation [111, 112]. Neutrophils can release lytic enzyme, produce ROS and generate neutrophil extracellular traps (NETs) [113]. Neutrophils are found as tumor-infiltrating cells (known as TANs) within the TIME [113], where they can be polarized towards the anti-tumor type-1 neutrophil (N1) subset, that promotes T cell-mediated tumor clearance, or pro-tumor N2-subsets, which act as immunosuppressive cells [113]. This phenotypic and functional switch of TANs could be linked to tumor stages and TME. Indeed, TANs switch and polarization is regulated by TGFβ, that induces tumor promoting N2 phenotype while, blockage of TGFβ stimulates anti-tumor function of TANs [113].

    In PCa TIME, neutrophils expressed IL-6R (CD126) and the high amount of IL-6 induces STAT3 signaling that regulates immunosuppressive features (Figure 2F) [114]. An in vitro study showed that NE, a serine protease stored in neutrophils, activates ERK signaling in a dose dependent manner and the AXL receptor tyrosine kinase in PCa cell lines, that acquired increased migratory capability (Figure 2G). TANs can also influence angiogenesis within PCa-TME and can support metastasis (Figure 2H). Using prostate cancer cells type 3 (PC-3) cell line, orthotopically injected in non-obese diabetes (NOD)/severe combined immunodeficiency (SCID) mice, it has been showed that both neutrophils and TANs are able to secrete higher amount of MMP-9, compared to macrophages and TAMs [115] and TANs-derived MMP-9 supports metastasis development [115]. Neutrophil function is modulated by microenvironmental and cancer-derived stimuli, such as sialic acid binding immunoglobulin like lectin (Siglec) ligands, which are upregulated in many cancers, including PCa [116]. These ligands can bind to the inhibitory CD33-related Siglecs and exert a negative immunomodulatory function. The lectin galactoside-binding soluble 3 binding protein (LGALS3BP), a ligand for human Siglec9, is upregulated in the ECM of PCa specimens and can inhibit neutrophils activation, supporting immune escape of cancer cells [116]. Diverse studies underlined a correlation between circulating neutrophils [in terms of neutrophils-to-lymphocytes ratio (NLR)] in PCa patients, and patients features as elevated NLR is associated with shorter OS in mCRPC subjects [117], while lower NLR in post-chemotherapy mCRPC patients is associated to longer OS [118]. The NLR value resulted to be increased also comparing PCa and benign prostatic hyperplasia (BPH) patients and is predictive of biochemical recurrence in patients with localized PCa after radical prostatectomy [117120]. These findings suggest a role of circulating neutrophils and TANs in determining disease progression and cancer development that still need to be fully elucidated.

    DCs

    DCs are known as the most powerful antigen presenting cells (APCs), being able to activate T cells but also to drive innate immune cells. DCs consist of three major cell subpopulations: myeloid conventional DCs1 (cDCs1), myeloid cDCs2, and plasmacytoid DCs (pDCs) [121]. cDCs1 exert the most potent anti-tumor functions resulting from the ability to release IL-12 and orchestrate anti-tumor CD8+ T cell effectors functions, through cross-presentation and induction of anti-tumor CD4+ Th1 type cells [121].

    Several experimental evidence has suggested the anti-tumor role played by DCs in PCa, however, during cancer development these cells appeared reduced in number and dysfunctional or immature, favoring a tolerogenic environment [122124]. Moreover, in PCa TME, it has been reported that VEGF was able to inhibit antigen presentation by DCs [125]. Given the potential therapeutic use of DCs, the first DC therapy was approved by the Food and Drug Administration (FDA) in 2010, the Sipuleucel-T in patients with the mCRPC [126]. A portion of mCRPC patients treated with this DC-based immunotherapy experienced improved OS, however most potent vaccines or combination therapies are needed to counteract the PCa immunosuppressive microenvironment and to implement immunotherapy [127].

    NK cells

    NK cells are large granular lymphocytes characterized by natural cytotoxicity against cancer cells, together with cytokines-producing effector functions [128131]. NK cells represent the 10–15% total human peripheral blood mononuclear cells [128131]. NK cells discriminate between healthy self-cells and infected or tumor cells trough activating/inhibiting receptors present on cellular membrane and their major histocompatibility complex (MHC) class I–specific receptors that finely regulate NK cells killing activity [128130]. NK cells recognize both self-ligands on stressed cells such as ULBP and MIC molecules and non-self-ligands, as well as TLR ligands, that instruct the production of IFNγ and cytotoxicity by NK cells [128130]. Moreover, NK cells can eliminate antibody-coated cells through the antibody-dependent cell cytotoxicity (ADCC) enabled by the expression of fragment crystallizable (Fc) receptor CD16 on the cell surface [128130].

    Depending on expression of the neural cell adhesion molecule (NCAM), namely CD56, and the low-affinity Fc receptor CD16, human NK cells exhibit different phenotype and functionalities and can be classified into two major cell subsets [128130]. CD56dimCD16+ NK cells constitute the 85–90% of both peripheral blood cytolytic NK cells, while cytokines-producing CD56brightCD16 account as the 10–15% of circulating NK cells [128130]. While CD56dimCD16+ NK cells express CXCR1 to allow their recruitment to peripheral inflammation area [132], CCR7 was found expressed on CD56brightCD16 to permit NK cells homing towards lymph nodes [133].

    Within the developing decidua, a third NK cell subset has been found, defined as CD56brigthtCD16 NK cells, characterized by tolerogenic functions for the developing fetus, together with pro-angiogenic functions, these latter necessary for the correct development of spiral artery [134, 135].

    NK cells have been found altered in their phenotype and functions in diverse solid and hematological cancers [136, 137]. In solid cancers, hypofunctional NK cells have been found both at tumor tissue and peripheral levels [136139]. As shared features of cell anergy in cancers, NK cells have been reported have decreased levels of NKG2D (a major activator receptor), together with impaired degranulation capabilities and reduced production and release of cytolytic molecules, such as perforin, granzymes, and IFNγ (Figure 2I) [136, 140]. NKG2D-deficient TRAMP mice exhibit three times fold increase in developing aggressive poorly differentiated prostate carcinoma, compared to NKG2D wild type (wt) TRAMP animals [141]. Moreover, in NKG2D wt TRAMP mice, progression to PD PCa was mostly associated with downregulation of NKG2D ligand expression by tumor cells [141].

    Several soluble factors present in the TME [142, 143], such as TGFβ, IL-6, adenosine (after hypoxia), prostaglandin E2 (PGE2), act as relevant players in shaping NK cell activities, including PCa. Also, the strong immunosuppressive microenvironment characterizing PCa impairs NK cell functions at multiple levels [144].

    In a first study, Pasero et al. [145] traced NK cells activities in the peripheral blood of patients with metastatic PCa, with 5 year-follow-up. Authors observed that PCa patients with longer time of castration response and OS displayed increased expression of activating receptors and high cytotoxicity by NK cells [145]. Natural cytotoxicity receptors (NCRs) NKp30 and NKp46 were found as the most predictive markers of OS and time to castration resistance in the cohort of patients analyzed [145]. Together, these results place NK cells as potential predictive biomarkers for the stratification of PCa patients having longer time of castration response, thus paving the way to explore therapies aimed at enhancing NK cells in metastatic PCa patients. Another study by Pasero et al. [144] showed that tumor infiltrating NK cells in PCa patients are enriched in immature CD56bright cells (Figure 2J) that, while expressing markers of activation, are poorly cytotoxic and that TGFβ, an immunosuppressive cytokine abundant in PCa tissues, strongly regulate this process. By performing NK cell-PCa cells co-culturing experiments, the authors showed that PCa cancer cells support the expression of ILT2/LILRB inhibitory receptor, together with downregulation of NKG2D, NKp46, and CD16 on NK cells, negatively impacting on NK-tumor cell recognition (Figure 2K) [144]. Interestingly, NKp46 was also reduced in PCa circulating NK cells [144].

    A study by Koo et al. [146] reported that reduction of CD56brightCD16 NK cells precede NK cell dysfunction in PCa patients. Authors observed that NK cell activation and the proportion of CD56bright NK cells were lower in PCa patients, compared to control subjects. Also, increased CD56dim to CD56bright ratio was detected in PCa patients that gradually increased in association with tumor staging [146].

    The JAK/STAT signaling is involved in PCa tumor suppression [147]. Combined inhibition of JAK1,2/STAT3-PD-L1 signaling pathways has been found to suppress CRPC immune escape to NK cell anti-tumor activities [147].

    In a study on 43 subjects undergoing prostate biopsy and using a liquid biopsy-based method, Barkin et al. [148] observed that low subjects with levels of NK cell activity were more likely to have a positive outcome at prostate biopsy.

    PCa circulating NK cells were also found to increase their expression of PD-1 and TIM-3 (as cell exhaustion markers), together with decreased level of NKG2D and degranulation capabilities, compared to circulating NK cells from control subjects (Figure 2L) [149]. Also, PCa circulating NK cells were found to increase their production of monocyte recruiting and macrophage polarizing factors that resulted in their capabilities to increase monocyte migration and M2-like/TAMs polarization, compared to circulating NK cells from healthy donors [149].

    The relevance of monocyte/macrophage-NK cell interactions in PCa has been demonstrated in a study showing that M2-like/TAM phenotype in tumor environment limit NK cells cytotoxicity against mCRPC cells, by enhancing the PD-L1 levels and reducing NKG2D ligands production through the IL-6/STAT3 pathway (Figure 2M) [150].

    IL-6, another abundant cytokine present both at tissue and systemic levels in PCa patients, limits NK cell anti-tumor activities, via STAT3 activation, by decreasing MICA/B and ULBPs NK cell-activating ligands, resulting in decrease NK cell killing capabilities. STAT3 activation in NK cells also results in reduced expression of activating receptors NKG2D, DNAM-1, IFNγ, and TNFα secretion [151]. However, IL-6 was demonstrated to not favor the decidual like CD56brightCD9+CD49a+NKG2Dlow phenotypic switch in healthy donor-derived NK cells. Finally, STAT3 was found to activate the Raf-MEK-ERK-AP-1 pathway which directly induces the expression of the TIGIT (Figure 2N) receptor belonging to the poliovirus receptor (PVR) family CD155, found increased in CRPC patients, resulting in poor survival [152] and high-risk recurrence after radical surgery [152].

    Pro-angiogenic decidual-like NK (dNK-like) cells, characterized by the CD56brightCD16VEGFhighCXCL8+IFNlow subset, has been found in tumor infiltrating and circulating NK cells in NSCLC [153], pleural effusion of patients with metastatic cancers [154] and CRC patients [155]. These dNK-like cells have been found to be induced by TGFβ, as also confirmed by experimental in vitro models of TGFβ polarized cytolytic NK cells [149, 153, 154, 156, 157].

    Recently, Gallazzi et al. [149] demonstrated that NK cells isolated from peripheral blood of PCa patients are polarized towards the CD56brightCD9+CD49a+CXCR4+ decidual-like phenotype and exhibit pro-angiogenic functions, inducing tube formation by endothelial cells, due to increased production of VEGF, CXCL8, CXCL12 by NK cells and their ability to polarize macrophages toward the M2-like/TAM phenotype (Figure 2O) [149].

    NK T cells

    NK T (NKT) cells represent heterogeneous innate-like T lymphocytes in both human and mice, that co-express both T cell receptor (TCR) and NK cell markers. NKT cells are able to recognize lipid antigens through CD1d molecule. NKT cells include two different subpopulations: type I and type II NKT cells, according to TCR rearrangements and glycolipid reactivity [158, 159]. Type I or invariant NKT (iNKT) cells can be stimulated by alpha-galactosylceramide (α-GalCer) and have an invariant TCRα chain rearrangement, while TCRβ chains present a restricted repertoire, and consist of three cellular subsets, named NKT1, NKT2, and NKT17, with similarities to Th1, Th2, and Th17 cell subsets, respectively. Type II NKT cells, are characterized by a higher variable repertoire of variable alpha region (Vα) rearrangements [160].

    iNKT cells were found to be key active anti-tumor effectors [161], whereas type II NKT cells, have rather a pro-tumor role, promoting growth and metastasis [160]. iNKT cells exert anti-tumor effector cell activities by producing several Th1 cytokines, i.e. IFNγ, TNFα, and by eliminating CD1d-expressing tumor cells, thus they represent a potential intriguing therapeutic cellular tool against cancer development and metastasis [162]. In addition, in patients with advanced PCa with elevated prostate-specific antigen (PSA) levels, peripheral blood iNKT cells were decreased in comparison to PCa patients with androgen withdrawal and stable PSA levels [163]. Also, in patients with androgen-independent advanced PCa, peripheral blood iNKT cell frequency was reduced [164], and results from in vitro activated iNKT with α-GalCer and autologous-irradiated PBMCs for 3–4 weeks, showed that PCa patients had iNKT with defective IFNγ production, compared to healthy controls, whereas IL-4 secretion was normal [164].

    In the spontaneous TRAMP model, iNKT cells infiltrate prostate tumor via CCL2/CCR5 pathway; however, tumor cells only partially activate iNKT cells, because of their impairment to release IFNγ [165]. Of note, this defect could be reverted both in vitro and in vivo by using combining IL-12 and α-GalCer [165]. Interestingly, studying Jalpha18 (Jα18)–/– mice, selectively deficient in iNKT cells, Bellone et al. [166] generated male TRAMP Jα18–/– mice, and found that tumor onset was accelerated and more aggressive comparing to TRAMP mice, indicating that iNKT play a relevant role in the immune surveillance of spontaneous TRAMP model.

    Finally, in the TRAMP model, iNKT were able to interact with TAMs in the TIME, kill pro-angiogenic tyrosine kinase with immunoglobulin (Ig) and epidermal growth factor (EGF) homology domains type 2+ (TIE2+) M2-like TAMs, and support M1-like macrophages [166]. This key process was modulated by engagement of CD1d, first apoptosis signal receptor (FAS), and CD40 molecules [166] and, of note, iNKT cell transfer into tumor-bearing mice resulted in tumor growth inhibition and decreased M2-like TAMs [166].

    Monocytes/Macrophages

    In TIME, the cellular subset recognized as TAMs represents the major component of immune system and plays a crucial role in shaping TIME and in both contrasting and contributing to tumor progression by modulating anti-tumor adaptive immune response, angiogenesis, growth and survival of cancer cells and metastasis formation [167]. Among TAMs two main polarized phenotypes are recognized: the classically activated M1-like and the alternatively activated M2-like that respectively expressed HLA-DR, CD80/86, and CD206, CD163, CD204, stabilin-1 [167, 168]. As commonly accepted, M1-like TAMs exert anti-tumoral activities improving activation of adaptive immune response, while M2-like TAMs support tumor growth by immune suppression, angiogenesis induction and metastasis promotion [167, 168].

    Cancer cell can escape the local immune control, giving origin to clones that can recruit circulating monocytes which play a crucial role in metastasis development and reprogram TAMs toward a M2-like phenotype [167, 169].

    As for many cancer types, inflammation is a driver in carcinogenesis. In PCa, TAMs are considered central modulators of malignant progression, metastasis formation and therapeutic response [170], thus different studies focused on the clinical and pathological significance of TAMs in prostate tissue.

    The M2-like TAM phenotype is driven by different stimuli within TME which include PGE2 [171], CCL2 [also known as monocyte chemoattractant protein 1 (MCP1)] produced by both cancer cells and CAFs in PCa [172], CSF-1 as well as GM-CSF and TGFβ produced by cancer and stromal cells which strongly contribute to macrophages polarization and immunosuppressive environment formation [173], CXCL12 and IL-6 (Figure 2P) [174]. This dialogue from cancer to macrophages is also maintained in the opposite direction as TAMs promote cancer progression stimulating migration and invasion by CCL22-CCR4 axis activation (Figure 2Q) [175]. Also, in PTEN null mouse model of PCa, high fat diet (HFD) mediates inflammation and induce M2-like phenotype switching with increased number of CD206+ TAMs [176]. Moreover, increased TAM-derived IL-6 pushes PCa growth upon STAT3 pathway activation [177]. This effect is reduced by colecoxib treatments only in mice fed HFD which showed reduced tumor growth and IL-6 production [177].

    STAT3 is a key factor involved in CCL5 effect on PCa cells. TAMs-derived CCL5 activates STAT3 signaling in cancer cells and increases cell migration, EMT and cell invasion as well as supports cancer stem cell self-renewal (Figure 2R) [178]. Silencing of CCL5 in TAMs suppressed PCa xenograft growth and bone metastasis formation as tumorigenicity of PCa stem cell in vivo [178]. Finally, in human, CCL5 expression correlates with Gleason score, poor prognosis, and metastasis formation [178]. Another mechanism that mediates cancer cell-macrophages crosstalk is driven by the recepteur d’origine nantais (RON) receptor [macrophage stimulating 1 receptor (MST1R)] which is a member of mesenchymal-epithelial transition factor (MET) family of receptor tyrosine kinases [179]. RON is overexpressed on PCa epithelial cells, and its expression correlates with poor prognosis and therapy resistance [179]. RON expressed by cancer epithelial cells mediates tumor growth and metastasis development by modulating macrophage phenotype toward the M2-like. Indeed, the loss of RON, selectively on prostate epithelial cells, induces transcriptional reprogramming on macrophages to support M1-like markers expression [179].

    Analysis of 131 biopsies of Japanese PCa patients reveals a positive association between abundance of CD68+ macrophages infiltrating the tumor mass and both serum level of PSA [180] and Gleason score [180]. Same conclusion derived from a cohort of 85 patients with prostate carcinoma from a Swedish study in which higher Gleason score correlates with increased density of CD68+ macrophages which also results as predictor of shorter cancer-specific survival (CSS) [181].

    Another association from the Japanese cohort involves TAMs count and the relapse-free survival rate, which is lower in patients with higher TAMs infiltration [180]. In an American study with 81 PCa patients, TAM density within tumor area positively correlates with Gleason score [182] as confirmed in a Turkish study involving 100 patients in which density of CD68+ TAMs infiltration even correlates with tumor stages, extracapsular extension and perineural invasion [183]. The positive association between Gleason score and TAMs number is further confirmed by tissue microarray analysis of 322 prostatectomy specimens in an American cohort in which the greater amount of CD68+ macrophages is detected in malignant areas in comparison to healthy tissues [184] and in a German cohort of over 400 patients [185]. An interesting mechanism in PCa-macrophages crosstalk involved semaphorin 3A (SEMA3A) which is produced by cancer cells and recruit monocytes to the tumor site where acquire a pro-tumoral CD68+ M2-like phenotype [186]. In this study, it has also been demonstrated that the increased expression of SEMA3A and number of CD68+ TAMs negatively correlate with disease-free survival times and disease recurrence [186].

    Finally, a microarray analysis comprising 9,393 samples from PCa patients demonstrates that the expression of TAMs-related signature is strongly associated with worse metastasis-free survival [187]. Of note, in a Norway cohort of 59 PCa patients, an increased count of CD68+ macrophage is observed in metastasis from lymph nodes, rectum, liver, and bladder as compared to primary tumors [188], suggesting a primarily involvement of macrophages not only in PCa progression but in metastasis formation and development.

    Clinical and pathological features of PCa patients displayed association not only with cell count but also with specific macrophage subtypes as results from an Italian cohort of 93 patients in which the amount of CD163+ TAMs are associated with extracapsular extension [189]. Increased infiltration of CD163+ TAMs also correlates with higher Gleason score (ranging from 8 to 10) as observed in two Swedish studies [190, 191] and the risk of death is twofold higher in patients with high infiltration of CD163+ TAMs as compared to those with a lower number of infiltrating TAMs [191].

    A novel TAM biomarker, chitinase-3-like protein 1 (CHI3L1, also known as YKL-40 enhances inflammation and angiogenesis within TME [167] and it has been detected at higher concentration in sera of 153 patients with metastatic PCa as compared to healthy subjects [167]. Moreover, in the same cohort of cancer patients, elevated plasma levels of YKL-40 at the time of diagnosis are predictor of a shorted OS [167].

    The influence of TAMs is also exerted on the therapeutic response of PCa patients as suggested by multiple evidence. Comparing hormone naïve and CRPC patients, the latter showed an increased number of CD68+ TAMs expressing cathepsin S which is involved in ECM remodeling and angiogenesis [192]. Analyzing surgery-derived specimens of pre-treated (cyproterone or leuprolide in combination with flutamide) and untreated patients, the first group displayed increased number of CD68+ TAMs [193], similarly to the increased amount of CD68+ and CD163+ TAMs observed in another cohort of pre-treated patients with Bicalutamide-based androgen deprivation therapy (ADT) [194] or with hormone ablation-treated patients (luteinizing hormone/releasing hormone-agonists and/or antiandrogen prior to surgery [195]. Also, the serum level of YKL-40 could also be considered as prognostic factors for CRPC management thus, the increasing of YKL-40 post-treatment is an independent prognostic factor of early death [193] and of shorter OS [196]. Moreover, another study with 362 PCa patients showed that subject with high M2-like TAMs infiltration displayed the worst prognosis and clinical features and the poorer response to the anti-PD-L1 treatment [197]. These data confirmed an active role of TAMs in modulating PCa progression and disease development also in relation to the adopted therapy and pointed TAMs as promising target to prevent disease recurrence and to improve patient outcomes.

    Conclusion

    Immunotherapy has revolutionized the therapeutic approach to cancer, placing the TIMEs as a relevant target for single agent and combination therapy able to reawaken the dormant, anergic immune cells infiltrating tumor tissues. Several strategies have been developed, that include immunocytokine therapies, adoptively transferred cell therapies, generation of chimeric antigen receptor-engineered T (CAR-T) cells and most recently CAR-NK cells. Some of these approaches resulted in relevant progress in cancer treatments, particularly in patients with hematological and some solid (melanoma, lung) cancers. Therefore, a relevant window of failure still persists in the field of immunotherapy, due to the tumor intrinsic and tumor extrinsic features of cancers. Tumors can limit the success of immunotherapy, and in particular in PCa, due to the high heterogeneity of the TME and the TIIME. As a relevant example in the field in this complex scenario, the plasticity of the immune cells, defined as their ability to adapt to the surrounding pathophysiological environment, still represent a challenge. This will culminate to the ability of tumor cells and TME to polarize immune cells, independently from their activation and differentiation state. This latter clearly suggests that an even more precise knowledge of the cellular and molecular mechanisms governing the immune cell response to cancers (e.g., immune cells polarization, immune cells/TME crosstalk) still urges, as a clinical unmet need, to better design successful and personalized immunotherapeutic approaches, to be combined with chemo/radio or targeted therapy and overcame tumor immune/escape and therapy resistance in PCa.

    Abbreviations

    AR:

    androgen receptor

    CCL2:

    C-C motif chemokine ligand 2

    CCR4:

    C-C motif chemokine receptor 4

    cDCs1:

    conventional dendritic cells 1

    CRPC:

    castration-resistant prostate cancer

    CSF-1:

    colony stimulating factor 1

    CXCL8:

    C-X-C motif chemokine ligand 8

    CXCR4:

    C-X-C motif chemokine receptor 4

    DCs:

    dendritic cells

    ECM:

    extracellular matrix

    EMT:

    epithelial-to-mesenchymal transition

    ERK1/2:

    extracellular signal-regulated kinase 1 and 2

    IFNγ:

    interferon gamma

    IL-6:

    interleukin-6

    IL-6R:

    interleukin-6 receptor

    iNKT:

    invariant natural killer T

    JAK:

    Janus kinase

    M2:

    type-2 macrophage

    mCRPC:

    metastatic castration-resistant prostate cancer

    MDSCs:

    myeloid-derived suppressor cells

    MICA/B:

    major histocompatibility complex-class I chain related proteins A and B

    M-MDSCs:

    monocytes-myeloid-derived suppressor cells

    MMPs:

    matrix metalloproteases

    NK:

    natural killer

    NKG2D:

    natural killer group 2D

    NKT:

    natural killer T

    NLR:

    neutrophils-to-lymphocytes ratio

    OS:

    overall survival

    PCa:

    prostate cancer

    PD-L1:

    programmed death-ligand 1

    PMN:

    polymorphonuclear

    PPARδ:

    peroxisome proliferator activated receptor delta

    PSA:

    prostate-specific antigen

    RON:

    recepteur d’origine Nantais

    Siglec:

    sialic acid binding immunoglobulin like lectin

    STAT:

    signal transducer and activator of transcription

    TAMs:

    tumor-associated macrophages

    TANs:

    tumor-associated neutrophils

    TCR:

    T cell receptor

    TGFβ:

    transforming growth factor-beta

    Th2:

    T helper 2

    TIIME:

    tumor innate immune microenvironment

    TIME:

    tumor immune microenvironment

    TLR9:

    Toll-like receptor 9

    TME:

    tumor microenvironment

    TRAMP:

    transgenic adenocarcinoma of the mouse prostate

    Treg:

    T regulatory

    ULBPs:

    UL16 binding proteins

    VEGF:

    vascular endothelial growth factor

    α-GalCer:

    alpha-galactosylceramide

    Declarations

    Author contributions

    Conceptualization: MTP, FD, PC, AB, LM. Text drafting and editing: MTP, MG, MC, FD, PC, AB, LM. Critical revision: MTP, MG, MC, FD, PC, AB, LM. Figure preparation: MC. Funds: AB, LM. All the authors read and approved the submitted version.

    Conflicts of interest

    The authors declare that they have no conflicts of interest.

    Ethical approval

    Not applicable

    Consent to participate

    Not applicable.

    Consent to publication

    Not applicable.

    Availability of data and materials

    Not applicable.

    Funding

    AB is recipient of a research grant funded by the Italian Association for Cancer Research (AIRC-MFAG, ID 22818) and a research grant funded by the Foundation Cariplo (ID 2019-1609). LM is recipient of Fondi di Ateneo per la Ricerca FAR 2020 and FAR 2021, University of Insubria, Varese, Italy. MTP was supported by Fondazione Umberto Veronesi. MG is a participant to PhD course in Life Sciences and Biotechnology at the University of Insubria, Varese, Italy and funded by the Italian Ministry of University and Research PRIN 2017 (ID: 2017NTK4HY). MC is a participant to PhD course in Experimental and Translational Medicine at the University of Insubria, Varese, Italy. This work has been supported by the Italian Ministry of Health Ricerca Corrente-IRCCS MultiMedica.

    Copyright

    © The Author(s) 2022.

    References

    Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:733. [DOI] [PubMed]
    Sartor O, de Bono JS. Metastatic prostate cancer. N Engl J Med. 2018;378:64557. [DOI] [PubMed]
    Yadav SS, Stockert JA, Hackert V, Yadav KK, Tewari AK. Intratumor heterogeneity in prostate cancer. Urol Oncol. 2018;36:34960. [DOI] [PubMed]
    Brady L, Kriner M, Coleman I, Morrissey C, Roudier M, True LD, et al. Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling. Nat Commun. 2021;12:1426. [DOI] [PubMed] [PMC]
    Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20:66280. [DOI] [PubMed]
    Sidaway P. Immunoscore provides a more accurate prognosis. Nat Rev Clin Oncol. 2018;15:471. [DOI] [PubMed]
    Movassaghi M, Chung R, Anderson CB, Stein M, Saenger Y, Faiena I. Overcoming immune resistance in prostate cancer: challenges and advances. Cancers (Basel). 2021;13:4757. [DOI] [PubMed] [PMC]
    Karan D, Thrasher JB, Lubaroff D. Prostate cancer: genes, environment, immunity and the use of immunotherapy. Prostate Cancer Prostatic Dis. 2008;11:2306. [DOI] [PubMed]
    Kano A. Tumor cell secretion of soluble factor(s) for specific immunosuppression. Sci Rep. 2015;5:8913. [DOI] [PubMed] [PMC]
    Boulter L, Bullock E, Mabruk Z, Brunton VG. The fibrotic and immune microenvironments as targetable drivers of metastasis. Br J Cancer. 2021;124:2736. [DOI] [PubMed] [PMC]
    Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51:2741. [DOI] [PubMed] [PMC]
    Albini A, Bruno A, Noonan DM, Mortara L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. 2018;9:527. [DOI] [PubMed] [PMC]
    Bruno A, Pagani A, Pulze L, Albini A, Dallaglio K, Noonan DM, et al. Orchestration of angiogenesis by immune cells. Front Oncol. 2014;4:131. [DOI] [PubMed] [PMC]
    Garner H, de Visser KE. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol. 2020;20:48397. [DOI] [PubMed]
    Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, et al. Tgf-Beta signaling in development. Sci STKE. 2007;2007:cm1. [DOI] [PubMed]
    Wu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16:32943. [DOI] [PubMed]
    Santibañez JF, Quintanilla M, Bernabeu C. TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011;121:23351. [DOI] [PubMed]
    Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, et al. Transforming growth factor-beta (TGF-β) signaling in cancer-a betrayal within. Front Pharmacol. 2022;13:791272. [DOI] [PubMed] [PMC]
    Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021;18:934. [DOI] [PubMed]
    Seoane J, Gomis RR. TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harb Perspect Biol. 2017;9:a022277. [DOI] [PubMed] [PMC]
    Padua D, Massagué J. Roles of TGFbeta in metastasis. Cell Res. 2009;19:89102. [DOI] [PubMed]
    Sun N, Taguchi A, Hanash S. Switching roles of TGF-β in cancer development: implications for therapeutic target and biomarker studies. J Clin Med. 2016;5:109. [DOI] [PubMed] [PMC]
    Massagué J. TGFbeta in cancer. Cell. 2008;134:21530. [DOI] [PubMed] [PMC]
    Her NG, Jeong SI, Cho K, Ha TK, Han J, Ko KP, et al. PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway. Cell Cycle. 2013;12:152135. [DOI] [PubMed] [PMC]
    Morton DM, Barrack ER. Modulation of transforming growth factor beta 1 effects on prostate cancer cell proliferation by growth factors and extracellular matrix. Cancer Res. 1995;55:2596602. [PubMed]
    Wikström P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate. 1998;37:1929. [DOI] [PubMed]
    Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation. Cell Mol Immunol. 2015;12:55865. [DOI] [PubMed] [PMC]
    Xu L, Kitani A, Strober W. Molecular mechanisms regulating TGF-β-induced Foxp3 expression. Mucosal Immunol. 2010;3:2308. [DOI] [PubMed] [PMC]
    Mirzaei S, Paskeh MDA, Saghari Y, Zarrabi A, Hamblin MR, Entezari M, et al. Transforming growth factor-beta (TGF-β) in prostate cancer: a dual function mediator? Int J Biol Macromol. 2022;206:43552. [DOI] [PubMed]
    Zhang Q, Yang XJ, Kundu SD, Pins M, Javonovic B, Meyer R, et al. Blockade of transforming growth factor-β signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. Mol Cancer Ther. 2006;5:173343. [DOI] [PubMed]
    Steinestel K, Eder S, Schrader AJ, Steinestel J. Clinical significance of epithelial-mesenchymal transition. Clin Transl Med. 2014;3:17. [DOI] [PubMed] [PMC]
    David JM, Dominguez C, Hamilton DH, Palena C. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel). 2016;4:22. [DOI] [PubMed] [PMC]
    Wang H, Fang R, Wang XF, Zhang F, Chen DY, Zhou B, et al. Stabilization of Snail through AKT/GSK-3β signaling pathway is required for TNF-α-induced epithelial-mesenchymal transition in prostate cancer PC3 cells. Eur J Pharmacol. 2013;714:4855. [DOI] [PubMed]
    Seol MA, Kim JH, Oh K, Kim G, Seo MW, Shin YK, et al. Interleukin-7 contributes to the invasiveness of prostate cancer cells by promoting epithelial-mesenchymal transition. Sci Rep. 2019;9:6917. [DOI] [PubMed] [PMC]
    Cai Q, Chen Y, Zhang D, Pan J, Xie Z, Ma S, et al. Loss of epithelial AR increase castration resistant stem-like prostate cancer cells and promotes cancer metastasis via TGF-β1/EMT pathway. Transl Androl Urol. 2020;9:101327. [DOI] [PubMed] [PMC]
    Huang G, Osmulski PA, Bouamar H, Mahalingam D, Lin CL, Liss MA, et al. TGF-β signal rewiring sustains epithelial-mesenchymal transition of circulating tumor cells in prostate cancer xenograft hosts. Oncotarget. 2016;7:7712437. [DOI] [PubMed] [PMC]
    Kim IY, Ahn HJ, Lang S, Oefelein MG, Oyasu R, Kozlowski JM, et al. Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin Cancer Res. 1998;4:162530. [PubMed]
    Reis ST, Pontes-Júnior J, Antunes AA, Sousa-Canavez JM, Abe DK, Cruz JA, et al. Tgf-β1 expression as a biomarker of poor prognosis in prostate cancer. Clinics (Sao Paulo). 2011;66:11437. [DOI] [PubMed] [PMC]
    Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011;2:38496. [DOI] [PubMed] [PMC]
    Culig Z, Puhr M. Interleukin-6 and prostate cancer: current developments and unsolved questions. Mol Cell Endocrinol. 2018;462:2530. [DOI] [PubMed]
    Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33:12748. [DOI] [PubMed] [PMC]
    Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22:3340. [DOI] [PubMed]
    Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int. 2014;113:98692. [DOI] [PubMed]
    Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, Edwards J. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer. 2007;97:37883. [DOI] [PubMed] [PMC]
    Smith DA, Kiba A, Zong Y, Witte ON. Interleukin-6 and oncostatin-M synergize with the PI3K/AKT pathway to promote aggressive prostate malignancy in mouse and human tissues. Mol Cancer Res. 2013;11:115965. [DOI] [PubMed] [PMC]
    Cardillo MR, Ippoliti F. IL-6, IL-10 and HSP-90 expression in tissue microarrays from human prostate cancer assessed by computer-assisted image analysis. Anticancer Res. 2006;26:340916. [PubMed]
    Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res. 2000;6:27026. [PubMed]
    Zhou J, Chen H, Wu Y, Shi B, Ding J, Qi J. Plasma IL-6 and TNF-α levels correlate significantly with grading changes in localized prostate cancer. Prostate. 2022;82:5319. [DOI] [PubMed]
    Spiotto MT, Chung TD. STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. Prostate. 2000;42:8898. [DOI] [PubMed]
    Albini A, Calabrone L, Carlini V, Benedetto N, Lombardo M, Bruno A, et al. Preliminary evidence for IL-10-induced ACE2 mRNA expression in lung-derived and endothelial cells: implications for SARS-Cov-2 ARDS pathogenesis. Front Immunol. 2021;12:718136. [DOI] [PubMed] [PMC]
    Hutchins AP, Diez D, Miranda-Saavedra D. The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genomics. 2013;12:48998. [DOI] [PubMed] [PMC]
    Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50:87191. [DOI] [PubMed]
    Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010;10:17081. [DOI] [PubMed]
    Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170:208195. [DOI] [PubMed] [PMC]
    Comi M, Amodio G, Gregori S. Interleukin-10-producing DC-10 is a unique tool to promote tolerance via antigen-specific T regulatory type 1 cells. Front Immunol. 2018;9:682. [DOI] [PubMed] [PMC]
    Bhattacharyya S, Sen P, Wallet M, Long B, Baldwin AS, Jr, Tisch R. Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. Blood. 2004;104:11009. [DOI] [PubMed]
    Castiello L, Sabatino M, Ren J, Terabe M, Khuu H, Wood LV, et al. Expression of CD14, IL10, and tolerogenic signature in dendritic cells inversely correlate with clinical and immunologic response to TARP vaccination in prostate cancer patients. Clin Cancer Res. 2017;23:335264. [DOI] [PubMed] [PMC]
    Mocellin S, Panelli M, Wang E, Rossi CR, Pilati P, Nitti D, et al. IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun. 2004;5:62130. [DOI] [PubMed]
    Jensen IJ, McGonagill PW, Butler NS, Harty JT, Griffith TS, Badovinac VP. NK cell-derived IL-10 supports host survival during sepsis. J Immunol. 2021;206:117180. [DOI] [PubMed] [PMC]
    Tarrio ML, Lee SH, Fragoso MF, Sun HW, Kanno Y, O’Shea JJ, et al. Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response. J Immunol. 2014;193:35463. [DOI] [PubMed] [PMC]
    Huang L, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Lee NA, Lee JJ, et al. Eosinophil-derived IL-10 supports chronic nematode infection. J Immunol. 2014;193:417887. [DOI] [PubMed] [PMC]
    Davoine F, Lacy P. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front Immunol. 2014;5:570. [DOI] [PubMed] [PMC]
    Lewkowicz N, Mycko MP, Przygodzka P, Ćwiklińska H, Cichalewska M, Matysiak M, et al. Induction of human IL-10-producing neutrophils by LPS-stimulated Treg cells and IL-10. Mucosal Immunol. 2016;9:36478. [DOI] [PubMed]
    Kasten KR, Muenzer JT, Caldwell CC. Neutrophils are significant producers of IL-10 during sepsis. Biochem Biophys Res Commun. 2010;393:2831. [DOI] [PubMed] [PMC]
    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683765. [DOI] [PubMed]
    Trinchieri G. Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med. 2007;204:23943. [DOI] [PubMed] [PMC]
    Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:2850. [DOI] [PubMed]
    Maynard CL, Weaver CT. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol Rev. 2008;226:21933. [DOI] [PubMed] [PMC]
    Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001;2:81622. [DOI] [PubMed]
    Huang S, Ullrich SE, Bar-Eli M. Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res. 1999;19:697703. [DOI] [PubMed]
    Chen L, Shi Y, Zhu X, Guo W, Zhang M, Che Y, et al. IL-10 secreted by cancer-associated macrophages regulates proliferation and invasion in gastric cancer cells via cMet/STAT3 signaling. Oncol Rep. 2019;42:595604. [DOI] [PubMed] [PMC]
    de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med. 1995;27:53741. [DOI] [PubMed]
    Bakir WA, Gaidan HA, Al-Kaabi MM. Immunohistochemical expression of interlukin10 (IL10) and heat shock protein-90 (HSP-90) in prostatic carcinoma. Indian J Pathol Microbiol. 2020;63:2304. [DOI] [PubMed]
    Shao N, Xu B, Mi YY, Hua LX. IL-10 polymorphisms and prostate cancer risk: a meta-analysis. Prostate Cancer Prostatic Dis. 2011;14:12935. [DOI] [PubMed]
    Samiea A, Yoon JSJ, Ong CJ, Zoubeidi A, Chamberlain TC, Mui AL. Interleukin-10 induces expression of neuroendocrine markers and PDL1 in prostate cancer cells. Prostate Cancer. 2020;2020:5305306. [DOI] [PubMed] [PMC]
    Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Vom Berg J, et al. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22:23746. [DOI] [PubMed] [PMC]
    Li J, Zhang L, Zhang J, Wei Y, Li K, Huang L, et al. Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin-23 receptor. Carcinogenesis. 2013;34:65866. [DOI] [PubMed]
    Baird AM, Leonard J, Naicker KM, Kilmartin L, O’Byrne KJ, Gray SG. IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer. Lung Cancer. 2013;79:8390. [DOI] [PubMed]
    Cam C, Karagoz B, Muftuoglu T, Bigi O, Emirzeoglu L, Celik S, et al. The inflammatory cytokine interleukin-23 is elevated in lung cancer, particularly small cell type. Contemp Oncol (Pozn). 2016;20:2159. [DOI] [PubMed] [PMC]
    Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491:2548. [DOI] [PubMed] [PMC]
    Lan F, Zhang L, Wu J, Zhang J, Zhang S, Li K, et al. IL-23/IL-23R: potential mediator of intestinal tumor progression from adenomatous polyps to colorectal carcinoma. Int J Colorectal Dis. 2011;26:15118. [DOI] [PubMed]
    Ljujic B, Radosavljevic G, Jovanovic I, Pavlovic S, Zdravkovic N, Milovanovic M, et al. Elevated serum level of IL-23 correlates with expression of VEGF in human colorectal carcinoma. Arch Med Res. 2010;41:1829. [DOI] [PubMed]
    Gangemi S, Minciullo P, Adamo B, Franchina T, Ricciardi GR, Ferraro M, et al. Clinical significance of circulating interleukin-23 as a prognostic factor in breast cancer patients. J Cell Biochem. 2012;113:21225. [DOI] [PubMed]
    Wolf AM, Rumpold H, Reimer D, Marth C, Zeimet AG, Wolf D. High IL-12 p35 and IL-23 p19 mRNA expression is associated with superior outcome in ovarian cancer. Gynecol Oncol. 2010;118:24450. [DOI] [PubMed]
    Khazaie K, Blatner NR, Khan MW, Gounari F, Gounaris E, Dennis K, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. 2011;30:4560. [DOI] [PubMed]
    Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018;559:3639. [DOI] [PubMed] [PMC]
    Wang JM, Shi L, Ma CJ, Ji XJ, Ying RS, Wu XY, et al. Differential regulation of interleukin-12 (IL-12)/IL-23 by Tim-3 drives TH17 cell development during hepatitis C virus infection. J Virol. 2013;87:437283. [DOI] [PubMed] [PMC]
    Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, et al. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood. 2010;115:538592. [DOI] [PubMed] [PMC]
    Gupta S, Pungsrinont T, Ženata O, Neubert L, Vrzal R, Baniahmad A. Interleukin-23 represses the level of cell senescence induced by the androgen receptor antagonists enzalutamide and darolutamide in castration-resistant prostate cancer cells. Horm Cancer. 2020;11:18290. [DOI] [PubMed] [PMC]
    Liu Z, Zhang JY, Yang YJ, Chang K, Wang QF, Kong YY, et al. High IL-23+ cells infiltration correlates with worse clinical outcomes and abiraterone effectiveness in patients with prostate cancer. Asian J Androl. 2022;24:14753. [DOI] [PubMed] [PMC]
    Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:54150. [DOI] [PubMed] [PMC]
    Moon TC, St Laurent CD, Morris KE, Marcet C, Yoshimura T, Sekar Y, et al. Advances in mast cell biology: new understanding of heterogeneity and function. Mucosal Immunol. 2010;3:11128. [DOI] [PubMed]
    Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;9:121523. [DOI] [PubMed] [PMC]
    Varricchi G, Galdiero MR, Loffredo S, Marone G, Iannone R, Marone G, et al. Are mast cells MASTers in cancer? Front Immunol. 2017;8:424. [DOI] [PubMed] [PMC]
    Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta. 2009;1796:1926. [DOI] [PubMed] [PMC]
    Komi DEA, Redegeld FA. Role of mast cells in shaping the tumor microenvironment. Clin Rev Allergy Immunol. 2020;58:31325. [DOI] [PubMed] [PMC]
    Theoharides TC, Conti P. Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol. 2004;25:23541. [DOI] [PubMed]
    Pittoni P, Colombo MP. The dark side of mast cell-targeted therapy in prostate cancer. Cancer Res. 2012;72:8315. [DOI] [PubMed]
    Brusa D, Simone M, Gontero P, Spadi R, Racca P, Micari J, et al. Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison. Int J Urol. 2013;20:9718. [DOI] [PubMed]
    Hossain DM, Pal SK, Moreira D, Duttagupta P, Zhang Q, Won H, et al. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res. 2015;21:377182. [DOI] [PubMed] [PMC]
    Johansson A, Rudolfsson S, Hammarsten P, Halin S, Pietras K, Jones J, et al. Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. Am J Pathol. 2010;177:103141. [DOI] [PubMed] [PMC]
    Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. [DOI] [PubMed] [PMC]
    Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:38. [DOI] [PubMed] [PMC]
    Dysthe M, Parihar R. Myeloid-derived suppressor cells in the tumor microenvironment. Adv Exp Med Biol. 2020;1224:11740. [DOI] [PubMed]
    Sanaei MJ, Salimzadeh L, Bagheri N. Crosstalk between myeloid-derived suppressor cells and the immune system in prostate cancer: MDSCs and immune system in prostate cancer. J Leukoc Biol. 2020;107:4356. [DOI] [PubMed]
    Haist M, Stege H, Grabbe S, Bros M. The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment. Cancers (Basel). 2021;13:210. [DOI] [PubMed] [PMC]
    Chen J, Sun HW, Yang YY, Chen HT, Yu XJ, Wu WC, et al. Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer. Signal Transduct Target Ther. 2021;6:4. [DOI] [PubMed] [PMC]
    Idorn M, Køllgaard T, Kongsted P, Sengeløv L, Thor Straten P. Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer. Cancer Immunol Immunother. 2014;63:117787. [DOI] [PubMed]
    Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 2016;6:8095. [DOI] [PubMed] [PMC]
    De Cicco P, Ercolano G, Ianaro A. The new era of cancer immunotherapy: targeting myeloid-derived suppressor cells to overcome immune evasion. Front Immunol. 2020;11:1680. [DOI] [PubMed] [PMC]
    Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:15975. [DOI] [PubMed]
    Liew PX, Kubes P. The neutrophil’s role during health and disease. Physiol Rev. 2019;99:122348. [DOI] [PubMed]
    Wang C, Zhang Y, Gao WQ. The evolving role of immune cells in prostate cancer. Cancer Lett. 2022;525:921. [DOI] [PubMed]
    Ene CV, Nicolae I, Geavlete B, Geavlete P, Ene CD. IL-6 signaling link between inflammatory tumor microenvironment and prostatic tumorigenesis. Anal Cell Pathol (Amst). 2022;2022:5980387. [DOI] [PubMed] [PMC]
    Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia. 2014;16:77188. [DOI] [PubMed] [PMC]
    Läubli H, Alisson-Silva F, Stanczak MA, Siddiqui SS, Deng L, Verhagen A, et al. Lectin galactoside-binding soluble 3 binding protein (LGALS3BP) is a tumor-associated immunomodulatory ligand for CD33-related Siglecs. J Biol Chem. 2014;289:3348191. [DOI] [PubMed] [PMC]
    Su S, Liu L, Li C, Zhang J, Li S. Prognostic role of pretreatment derived neutrophil to lymphocyte ratio in urological cancers: a systematic review and meta-analysis. Int J Surg. 2019;72:14653. [DOI] [PubMed]
    Nuhn P, Vaghasia AM, Goyal J, Zhou XC, Carducci MA, Eisenberger MA, et al. Association of pretreatment neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel. BJU Int. 2014;114:E117. [DOI] [PubMed] [PMC]
    Tanik S, Albayrak S, Zengin K, Borekci H, Bakirtas H, Imamoglu MA, et al. Is the neutrophil-lymphocyte ratio an indicator of progression in patients with benign prostatic hyperplasia? Asian Pac J Cancer Prev. 2014;15:63759. [DOI] [PubMed]
    Wang S, Ji Y, Chen Y, Du P, Cao Y, Yang X, et al. The values of systemic immune-inflammation index and neutrophil-lymphocyte ratio in the localized prostate cancer and benign prostate hyperplasia: a retrospective clinical study. Front Oncol. 2021;11:812319. [DOI] [PubMed] [PMC]
    Murphy TL, Murphy KM. Dendritic cells in cancer immunology. Cell Mol Immunol. 2022;19:313. [DOI] [PubMed] [PMC]
    Mihalyo MA, Hagymasi AT, Slaiby AM, Nevius EE, Adler AJ. Dendritic cells program non-immunogenic prostate-specific T cell responses beginning at early stages of prostate tumorigenesis. Prostate. 2007;67:53646. [DOI] [PubMed] [PMC]
    Sciarra A, Lichtner M, Autran GA, Mastroianni C, Rossi R, Mengoni F, et al. Characterization of circulating blood dendritic cell subsets DC123+ (lymphoid) and DC11C+ (myeloid) in prostate adenocarcinoma patients. Prostate. 2007;67:17. [DOI] [PubMed]
    Mastelic-Gavillet B, Sarivalasis A, Lozano LE, Wyss T, Inoges S, de Vries IJM, et al. Quantitative and qualitative impairments in dendritic cell subsets of patients with ovarian or prostate cancer. Eur J Cancer. 2020;135:17382. [DOI] [PubMed]
    Bai WK, Zhang W, Hu B. Vascular endothelial growth factor suppresses dendritic cells function of human prostate cancer. Onco Targets Ther. 2018;11:126774. [DOI] [PubMed] [PMC]
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:41122. [DOI] [PubMed]
    Sutherland SIM, Ju X, Horvath LG, Clark GJ. Moving on from Sipuleucel-T: new dendritic cell vaccine strategies for prostate cancer. Front Immunol. 2021;12:641307. [DOI] [PubMed] [PMC]
    Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187376. [DOI] [PubMed] [PMC]
    Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9:50310. [DOI] [PubMed]
    Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:63340. [DOI] [PubMed]
    Parisi L, Bassani B, Tremolati M, Gini E, Farronato G, Bruno A. Natural killer cells in the orchestration of chronic inflammatory diseases. J Immunol Res. 2017;2017:4218254. [DOI] [PubMed] [PMC]
    Parolini S, Santoro A, Marcenaro E, Luini W, Massardi L, Facchetti F, et al. The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues. Blood. 2007;109:362532. [DOI] [PubMed]
    Kim CH, Pelus LM, Appelbaum E, Johanson K, Anzai N, Broxmeyer HE. CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56+ CD16 NK cells and late stage lymphoid progenitors. Cell Immunol. 1999;193:22635. [DOI] [PubMed]
    Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. 2003;198:120112. [DOI] [PubMed] [PMC]
    Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12:106574. [DOI] [PubMed]
    Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020;19:120. [DOI] [PubMed] [PMC]
    Chan IS, Ewald AJ. The changing role of natural killer cells in cancer metastasis. J Clin Invest. 2022;132:e143762. [DOI] [PubMed] [PMC]
    Cózar B, Greppi M, Carpentier S, Narni-Mancinelli E, Chiossone L, Vivier E. Tumor-infiltrating natural killer cells. Cancer Discov. 2021;11:3444. [DOI] [PubMed] [PMC]
    Bassani B, Baci D, Gallazzi M, Poggi A, Bruno A, Mortara L. Natural killer cells as key players of tumor progression and angiogenesis: old and novel tools to divert their pro-tumor activities into potent anti-tumor effects. Cancers (Basel). 2019;11:461. [DOI] [PubMed] [PMC]
    Zhang W, Zhao Z, Li F. Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy. Mol Immunol. 2022;144:5870. [DOI] [PubMed]
    Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008;28:57180. [DOI] [PubMed] [PMC]
    Baginska J, Viry E, Paggetti J, Medves S, Berchem G, Moussay E, et al. The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Front Immunol. 2013;4:490. [DOI] [PubMed] [PMC]
    Hasmim M, Messai Y, Ziani L, Thiery J, Bouhris JH, Noman MZ, et al. Critical role of tumor microenvironment in shaping NK cell functions: implication of hypoxic stress. Front Immunol. 2015;6:482. [DOI] [PubMed] [PMC]
    Pasero C, Gravis G, Guerin M, Granjeaud S, Thomassin-Piana J, Rocchi P, et al. Inherent and tumor-driven immune tolerance in the prostate microenvironment impairs natural killer cell antitumor activity. Cancer Res. 2016;76:215365. [DOI] [PubMed]
    Pasero C, Gravis G, Granjeaud S, Guerin M, Thomassin-Piana J, Rocchi P, et al. Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer. Oncotarget. 2015;6:1436073. [DOI] [PubMed] [PMC]
    Koo KC, Shim DH, Yang CM, Lee SB, Kim SM, Shin TY, et al. Reduction of the CD16CD56bright NK cell subset precedes NK cell dysfunction in prostate cancer. PLoS One. 2013;8:e78049. [DOI] [PubMed] [PMC]
    Xu LJ, Ma Q, Zhu J, Li J, Xue BX, Gao J, et al. Combined inhibition of JAK1,2/Stat3-PD-L1 signaling pathway suppresses the immune escape of castration-resistant prostate cancer to NK cells in hypoxia. Mol Med Rep. 2018;17:811120. [DOI] [PubMed] [PMC]
    Barkin J, Rodriguez-Suarez R, Betito K. Association between natural killer cell activity and prostate cancer: a pilot study. Can J Urol. 2017;24:870813. [PubMed]
    Gallazzi M, Baci D, Mortara L, Bosi A, Buono G, Naselli A, et al. Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production and secrete monocyte-recruiting and polarizing factors. Front Immunol. 2021;11:586126. [DOI] [PubMed] [PMC]
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399416. [DOI] [PubMed] [PMC]
    Cacalano NA. Regulation of natural killer cell function by STAT3. Front Immunol. 2016;7:128. [DOI] [PubMed] [PMC]
    Lv D, Wu X, Chen X, Yang S, Chen W, Wang M, et al. A novel immune-related gene-based prognostic signature to predict biochemical recurrence in patients with prostate cancer after radical prostatectomy. Cancer Immunol Immunother. 2021;70:3587602. [DOI] [PubMed]
    Bruno A, Focaccetti C, Pagani A, Imperatori AS, Spagnoletti M, Rotolo N, et al. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia. 2013;15:13342. [DOI] [PubMed] [PMC]
    Bosi A, Zanellato S, Bassani B, Albini A, Musco A, Cattoni M, et al. Natural killer cells from malignant pleural effusion are endowed with a decidual-like proangiogenic polarization. J Immunol Res. 2018;2018:2438598. [DOI] [PubMed] [PMC]
    Bruno A, Bassani B, D’Urso DG, Pitaku I, Cassinotti E, Pelosi G, et al. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer. FASEB J. 2018;32:536577. [DOI] [PubMed]
    Cerdeira AS, Rajakumar A, Royle CM, Lo A, Husain Z, Thadhani RI, et al. Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol. 2013;190:393948. [DOI] [PubMed] [PMC]
    Albini A, Gallazzi M, Palano MT, Carlini V, Ricotta R, Bruno A, et al. TIMP1 and TIMP2 downregulate TGFβ induced decidual-like phenotype in natural killer cells. Cancers (Basel). 2021;13:4955. [DOI] [PubMed] [PMC]
    Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H. The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol. 2003;21:483513. [DOI] [PubMed]
    Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol. 2004;4:2317. [DOI] [PubMed]
    Berzofsky JA, Terabe M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J Immunol. 2008;180:362735. [DOI] [PubMed]
    Exley MA, Dellabona P, Casorati G. Exploiting CD1-restricted T cells for clinical benefit. Mol Immunol. 2021;132:12631. [DOI] [PubMed]
    Terabe M, Berzofsky JA. Tissue-specific roles of NKT cells in tumor immunity. Front Immunol. 2018;9:1838. [DOI] [PubMed] [PMC]
    Schwemmer B. Natural killer T cells in patients with prostatic carcinoma. Urol Int. 2003;71:1469. [DOI] [PubMed]
    Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, et al. Loss of IFN-gamma production by invariant NK T cells in advanced cancer. J Immunol. 2001;167:404650. [DOI] [PubMed]
    Nowak M, Arredouani MS, Tun-Kyi A, Schmidt-Wolf I, Sanda MG, Balk SP, et al. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with alpha-galactosylceramide. PLoS One. 2010;5:e11311. [DOI] [PubMed] [PMC]
    Bellone M, Ceccon M, Grioni M, Jachetti E, Calcinotto A, Napolitano A, et al. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS One. 2010;5:e8646. [DOI] [PubMed] [PMC]
    Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, et al. Tumor-associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Front Oncol. 2020;10:566511. [DOI] [PubMed] [PMC]
    Cassetta L, Pollard JW. Tumor-associated macrophages. Curr Biol. 2020;30:R2468. [DOI] [PubMed]
    Loyher PL, Hamon P, Laviron M, Meghraoui-Kheddar A, Goncalves E, Deng Z, et al. Macrophages of distinct origins contribute to tumor development in the lung. J Exp Med. 2018;215:253653. [DOI] [PubMed] [PMC]
    Tyekucheva S, Bowden M, Bango C, Giunchi F, Huang Y, Zhou C, et al. Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer. Nat Commun. 2017;8:420. [DOI] [PubMed] [PMC]
    Luan B, Yoon YS, Le Lay J, Kaestner KH, Hedrick S, Montminy M. CREB pathway links PGE2 signaling with macrophage polarization. Proc Natl Acad Sci U S A. 2015;112:156427. [DOI] [PubMed] [PMC]
    Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010;102:5228. [DOI] [PubMed] [PMC]
    Hayashi T, Fujita K, Matsushita M, Nonomura N. Main inflammatory cells and potentials of anti-inflammatory agents in prostate cancer. Cancers (Basel). 2019;11:1153. [DOI] [PubMed] [PMC]
    Hatano K, Fujita K, Nonomura N. Application of anti-inflammatory agents in prostate cancer. J Clin Med. 2020;9:2680. [DOI] [PubMed] [PMC]
    Maolake A, Izumi K, Shigehara K, Natsagdorj A, Iwamoto H, Kadomoto S, et al. Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis. Oncotarget. 2017;8:973951. [DOI] [PubMed] [PMC]
    Haase J, Weyer U, Immig K, Klöting N, Blüher M, Eilers J, et al. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia. 2014;57:56271. [DOI] [PubMed]
    Hayashi T, Fujita K, Nojima S, Hayashi Y, Nakano K, Ishizuya Y, et al. High-fat diet-induced inflammation accelerates prostate cancer growth via IL6 signaling. Clin Cancer Res. 2018;24:430918. [DOI] [PubMed]
    Huang R, Wang S, Wang N, Zheng Y, Zhou J, Yang B, et al. CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling. Cell Death Dis. 2020;11:234. [DOI] [PubMed] [PMC]
    Sullivan C, Brown NE, Vasiliauskas J, Pathrose P, Starnes SL, Waltz SE. Prostate epithelial RON signaling promotes M2 macrophage activation to drive prostate tumor growth and progression. Mol Cancer Res. 2020;18:124454. [DOI] [PubMed] [PMC]
    Nonomura N, Takayama H, Nakayama M, Nakai Y, Kawashima A, Mukai M, et al. Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer. BJU Int. 2011;107:191822. [DOI] [PubMed]
    Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol. 2000;17:44551. [DOI] [PubMed]
    Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res. 2000;60:585761. [PubMed]
    Ok Atïlgan A, Özdemir BH, Akçay EY, Ataol Demirkan Ö, Tekindal MA, Özkardeş H. Role of tumor-associated macrophages in the Hexim1 and TGFβ/SMAD pathway, and their influence on progression of prostatic adenocarcinoma. Pathol Res Pract. 2016;212:8392. [DOI] [PubMed]
    Gollapudi K, Galet C, Grogan T, Zhang H, Said JW, Huang J, et al. Association between tumor-associated macrophage infiltration, high grade prostate cancer, and biochemical recurrence after radical prostatectomy. Am J Cancer Res. 2013;3:5239. [PubMed] [PMC]
    Jones JD, Sinder BP, Paige D, Soki FN, Koh AJ, Thiele S, et al. Trabectedin reduces skeletal prostate cancer tumor size in association with effects on M2 macrophages and efferocytosis. Neoplasia. 2019;21:17284. [DOI] [PubMed] [PMC]
    Liu F, Wang C, Huang H, Yang Y, Dai L, Han S, et al. SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance. Cell Mol Immunol. 2021;18:7524. [DOI] [PubMed] [PMC]
    Zhao SG, Lehrer J, Chang SL, Das R, Erho N, Liu Y, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst. 2019;111:30110. [DOI] [PubMed]
    Richardsen E, Uglehus RD, Due J, Busch C, Busund LT. The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma. Histopathology. 2008;53:308. [DOI] [PubMed]
    Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33:242331. [DOI] [PubMed]
    Lundholm M, Hägglöf C, Wikberg ML, Stattin P, Egevad L, Bergh A, et al. Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions. Sci Rep. 2015;5:15651. [DOI] [PubMed] [PMC]
    Erlandsson A, Carlsson J, Lundholm M, Fält A, Andersson SO, Andrén O, et al. M2 macrophages and regulatory T cells in lethal prostate cancer. Prostate. 2019;79:3639. [DOI] [PubMed] [PMC]
    Lindahl C, Simonsson M, Bergh A, Thysell E, Antti H, Sund M, et al. Increased levels of macrophage-secreted cathepsin S during prostate cancer progression in TRAMP mice and patients. Cancer Genomics Proteomics. 2009;6:14959. [PubMed]
    Cao J, Liu J, Xu R, Zhu X, Zhao X, Qian BZ. Prognostic role of tumour-associated macrophages and macrophage scavenger receptor 1 in prostate cancer: a systematic review and meta-analysis. Oncotarget. 2017;8:832619. [DOI] [PubMed] [PMC]
    Liu Q, Tong D, Liu G, Gao J, Wang LA, Xu J, et al. Metformin inhibits prostate cancer progression by targeting tumor-associated inflammatory infiltration. Clin Cancer Res. 2018;24:562234. [DOI] [PubMed]
    Escamilla J, Schokrpur S, Liu C, Priceman SJ, Moughon D, Jiang Z, et al. CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. Cancer Res. 2015;75:95062. [DOI] [PubMed] [PMC]
    Darr C, Krafft U, Hadaschik B, Tschirdewahn S, Sevcenco S, Csizmarik A, et al. The role of YKL-40 in predicting resistance to docetaxel chemotherapy in prostate cancer. Urol Int. 2018;101:6573. [DOI] [PubMed]
    Zhou JW, Dou CX, Liu CD, Liu Y, Yang JK, Duan HF, et al. M2 subtype tumor associated macrophages (M2-TAMs) infiltration predicts poor response rate of immune checkpoint inhibitors treatment for prostate cancer. Ann Med. 2021;53:73040. [DOI] [PubMed] [PMC]