TY - JOUR
T1 - PVRIG and PVRL2 are induced in cancer and inhibit CD8 + T-cell function
AU - Whelan, Sarah
AU - Ophir, Eran
AU - Kotturi, Maya F.
AU - Levy, Ofer
AU - Ganguly, Sudipto
AU - Leung, Ling
AU - Vaknin, Ilan
AU - Kumar, Sandeep
AU - Dassa, Liat
AU - Hansen, Kyle
AU - Bernados, David
AU - Murter, Benjamin
AU - Soni, Abha
AU - Taube, Janis M.
AU - Fader, Amanda Nickles
AU - Wang, Tian Li
AU - Shih, Ie Ming
AU - White, Mark
AU - Pardoll, Drew M.
AU - Liang, Spencer C.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-18-0442
DO - 10.1158/2326-6066.CIR-18-0442
M3 - Article
C2 - 30659054
AN - SCOPUS:85060948548
SN - 2326-6066
VL - 7
SP - 257
EP - 268
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 2
ER -