Figure 5.

Effects of dual blockade of T cell immunoreceptor with Ig and ITIM domains (TIGIT) and PD-(L)1 on antitumor immune responses. Left: Tumor-reactive CD8⁺ T cells encounter various immunosuppressive mechanisms (denoted by ‘-’) mediated by TIGIT and PD-1. In addition to inhibiting CD8⁺ T cells, TIGIT also inhibits NK cell activity. TIGIT signaling supports Treg suppressive function. Additionally, myeloid cells such as antigen-presenting cells contribute to a suppressive tumor microenvironment through release of cytokines such as IL-10 and TGF-β following PVR engagement of TIGIT. Tumor cells also express PVR and may contribute to immune suppression. Right: Anti-TIGIT combined with anti-PD-L1 reverses immunosuppression and modulates the tumor microenvironment to support antitumor responses (denoted by ‘+’). Dual blockade of TIGIT and PD-(L)1 allows costimulatory activation by CD28 and CD226 for fully competent CD8⁺ T cell effector activity. Release of CD226 from TIGIT restraint enhances NK cell activity. Treg suppression is impaired through blockade of TIGIT, and CD226 may promote a proinflammatory phenotype. Anti-TIGIT mAbs with an effector competent Fc capable of engaging Fcγ receptors (FcγR) allow additional mechanisms such as ADCC mediated by NK cells and ADCP mediated by macrophages that may lead to depletion of cells expressing high levels of TIGIT such as Tregs. In addition, Fc-FcγR interaction may modulate myeloid cells to relieve suppression and promote inflammatory conditions. The effects of CD226 engagement of PVR on tumor cells remains to be determined (denoted by ‘?’). NK, natural killer.