Immune checkpoint inhibitors and reproductive failures.

The human conceptus is a semi-allograft, which is antigenically foreign to the mother. Hence, the implantation process needs mechanisms to prevent allograft rejection during successful pregnancy. Immune checkpoints are a group of inhibitory pathways expressed on the surface of various immune cells in the form of ligand receptors. Immune cells possess these pathways to regulate the magnitude of immune responses and induce maternal-fetal tolerance. Briefly, 1) CTLA-4 can weaken T cell receptor (TCR) signals and inhibit T cell response; 2) The PD-1/PD-L1 pathway can reduce T cell proliferation, enhance T cell anergy and fatigue, reduce cytokine production, and increase T regulatory cell activity to complete the immunosuppression; 3) TIM3 interacts with T cells by binding Gal-9, weakening Th1 cell-mediated immunity and T cell apoptosis; 4) The LAG-3 binding to MHC II can inhibit T cell activation by interfering with the binding of CD4 to MHC II, and; 5) TIGIT can release inhibitory signals to NK and T cells through the ITIM structure of its cytoplasmic tail. Therefore, dysregulated immune checkpoints or the application of immune checkpoint inhibitors may impair human reproduction. This review intends to deliver a comprehensive overview of immune checkpoints in pregnancy, including CTLA-4, PD-1/PD-L1, TIM-3, LAG-3, TIGIT, and their inhibitors, reviewing their roles in normal and pathological human pregnancies.