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

Cancer Immunol Res. 2019 Feb;7(2):257-268. doi: 10.1158/2326-6066.CIR-18-0442. Epub 2019 Jan 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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