The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8 + T Cell Effector Function

Abstract

Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

“…This improvement in therapeutic efficacy following dual blockade of the TIGIT and PD-1 pathways has been demonstrated in the murine colorectal model. 21 In the clinical setting, the survival benefit we observed following delayed anti-TIGIT antibody administration may be promising for achieving disease control for patients with late diagnosis. We also investigated the presence of immunologic memory following treatment by re-challenging long-term survivors with tumor cell injection in the contralateral hemisphere.…”

“…Likewise, TIGIT expression on TILs has been shown to be upregulated in other solid cancers such as melanoma, colon cancer, and NSCLC in both mice and humans. 19-21 Moreover, it has been suggested that TIGIT expression may indicate dysfunction of CD8 + TILs and reduced effector function. 19 , 20 , 22 These results support the notion of using anti-TIGIT antibody in cancer treatment.…”

“…These findings were consistent with a prior study in murine CT26 colorectal cancer, during which anti-TIGIT treatment was initiated two weeks following tumor implantation. 21 Interestingly, an increase in survival was observed in the setting of B16-F10 melanoma using TIGIT deficient mice. 20 The differences in these findings may be explained by the degree of TIGIT depletion using anti-TIGIT antibodies versus germline deletion.…”

“…Similarly, Johnston et al (2014) also revealed higher IFNγ production following PD-1 and TIGIT dual-blockade. 21 In light of the survival benefit following TIGIT and PD-1 dual blockade, the elevated expression of pro-inflammatory cytokines may contribute to the mechanism(s) underlying the therapeutic efficacy.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Dual blockade of 2 immune checkpoints enhance function of tumor infiltrating lymphocytes (TILs) and tumor antigen-specific CD8 þ T cells, thereby, results in significant tumor rejection. 33,34 Lymphocyte activation gene-3 (LAG3) is an immune checkpoint upregulated on activated T cells, T reg , and NK cells. As a homologue to CD4, LAG3 expressed on effector CD4 þ T cells is deemed as a negative modulator tending to have interaction with major histocompatibility complex (MHC) II molecules.…”