From:  Role of immune checkpoint inhibitors in breast cancer and hematological malignancies

 The relationship between immune checkpoints and Tex.

Immune checkpointCentral roleAssociation with the Tex phenotypeClinical strategies
PD-1Binding to ligands PD-L1/PD-L2, it inhibits pathways such as PI3K/Akt and MAPK, thereby blocking the activation signals of T cellsA characteristic molecule of Tex. PD-1 positive T cells are often accompanied by functional defects (cell toxicity ↓, secretion of IFN-γ/IL-2 ↓)Anti-PD-1 monoclonal antibodies (pembrolizumab, nivolumab)
Anti-PD-L1 antibodies (atezolizumab)
CTLA-4Competitive binding to the surface of APC CD80/CD86, blocking the CD28-mediated co-stimulatory signal, inhibiting the early activation of T cellsInitiation process of participation depletionAnti-CTLA-4 antibodies (ipilimumab)
LAG-3Combined with MHC-II molecules and ligand FGL1, it inhibits TCR signal transductionTex’s “depth depletion” indicatorAnti-LAG-3 antibodies (relatlimab)
TIM-3Combined with ligands such as Gal-9 and CEACAM1, it inhibits the NF-κB pathway and induces T cell apoptosisTIM-3 positive cells lose their ability to secrete cytokines and have a poor response to single-agent ICIsAnti-TIM-3 antibody (MBG453)
Combination with other checkpoint inhibitors (PD-1/LAG-3)
TIGITCompetes with CD226 for the binding ligand CD155, blocks the co-stimulatory signal, and inhibits T cell activation
Highly expressed in Tex, co-localizes with PD-1		The levels of granzyme B and perforin in TIGIT positive Tex cells were reducedAnti-TIGIT antibody (tiragolumab)
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Tex: T cell exhaustion; PD-1: programmed death-1; PD-L1: programmed cell death ligand 1; IFN-γ: interferon-gamma; CTLA-4: cytotoxic T lymphocyte-associated protein 4; APC: antigen-presenting cell; LAG-3: lymphocyte activation gene-3; MHC: major histocompatibility complex; FGL1: fibrinogen like protein 1; TCR: T cell receptor; TIM-3: T cell immunoglobulin and mucin-domain containing protein 3; Gal-9: galectin-9; CEACAM1: carcino-embryonic antigen related cellular adhesion molecule 1; ICIs: immune checkpoint inhibitors; TIGIT: T cell immunoreceptor with Ig and ITIM domains.