PVRIG and PVRL2 are induced in cancer and inhibit CD8 + T-cell function

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)257-268
Number of pages12
JournalCancer Immunology Research
Volume7
Issue number2
DOIs
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Whelan, S., Ophir, E., Kotturi, M. F., Levy, O., Ganguly, S., Leung, L., Vaknin, I., Kumar, S., Dassa, L., Hansen, K., Bernados, D., Murter, B., Soni, A., Taube, J. M., Fader, A. N., Wang, T. L., Shih, I. M., White, M., Pardoll, D. M., & Liang, S. C. (2019). PVRIG and PVRL2 are induced in cancer and inhibit CD8 + T-cell function Cancer Immunology Research, 7(2), 257-268. https://doi.org/10.1158/2326-6066.CIR-18-0442