PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function.

Abstract

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. 244.

• Authors: Sarah Whelan, Eran Ophir, Maya F Kotturi, Ofer Levy, Sudipto Ganguly, Ling Leung, Ilan Vaknin, Sandeep Kumar, Liat Dassa, Kyle Hansen, David Bernados, Benjamin Murter, Abha Soni, Janis M Taube, Amanda Nickles Fader, Tian-Li Wang, Ie-Ming Shih, Mark White, Drew M Pardoll, Spencer C Liang
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 2 Pg. 257-268 (02 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 30659054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• NECTIN2 protein, human
• Nectins
• PDCD1 protein, human
• PVRIG protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Cell Surface
• Receptors, Immunologic
• TIGIT protein, human

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphocyte Activation (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology)
• Mice
• Nectins (metabolism)
• Neoplasms (genetics, immunology, metabolism, pathology)
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Protein Binding
• Receptors, Cell Surface (metabolism)
• Receptors, Immunologic (genetics, metabolism)
• Signal Transduction