Investigating nectin family receptors, Whelan et al. found that PVRIG and TIGIT (but not CD96) inhibit cytokine production and cytotoxic activity in human CD8+ T cells via non-redundant pathways (PVRIG/PVRL2 and TIGIT/PVR). Single or combination blockade of PVRIG, TIGIT, and PD-1 increased IFNγ production by human TILs, with triple blockade yielding the highest increase. In various human cancer types, PVRIG expression was upregulated on TILs (in line with TIGIT and PD-1), and PVRL2 was upregulated on cancer cells and TAMs. PVRIG was regulated through complex mechanisms, including rapid internalization in the absence of TCR stimulation.
Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8(+) T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG-PVRL2 pathway is a nonredundant signaling node. A combination of PVRIG blockade with TIGIT or PD-1 blockade further increased T-cell activation. In human tumors, PVRIG expression on T cells was increased relative to normal tissue and trended with TIGIT and PD-1 expression. Tumor cells coexpressing PVR and PVRL2 were observed in multiple tumor types, with highest coexpression in endometrial cancers. Tumor cells expressing either PVR or PVRL2 were also present in numbers that varied with the cancer type, with ovarian cancers having the highest percentage of PVR(-)PVRL2(+) tumor cells and colorectal cancers having the highest percentage of PVR(+)PVRL2(-) cells. To demonstrate a role of PVRIG and TIGIT on tumor-derived T cells, we examined the effect of PVRIG and TIGIT blockade on human tumor-infiltrating lymphocytes. For some donors, blockade of PVRIG increased T-cell function, an effect enhanced by combination with TIGIT or PD-1 blockade. In summary, we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways.See related article on p.