VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer

Abstract

To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.

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Figure 1: Treatment with ipilimumab increases immune cell infiltration, as well as expression of PD-L1 and VISTA in prostate tumors.
Figure 2: PD-L1+ and VISTA+ macrophages (CD68+) manifest an M2 phenotype and suppress T cell function.

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Acknowledgements

We thank the clinical and research team for this study, including P. Corn, J. Araujo, B. Chapin, S. Matin, A. Zurita-Saavedra, J. Davis, L. Pisters, and A. Aparicio for treatment and care of patients. We thank M. Campbell for assistance with clinical data collection; L. Xiong, B. Guan, J. Kim, M. Higa, J. Bustillos, D. Ng Tang, and S. Basu for technical support; M. Curran and M. Ai for help with the TRAMP-C2 mouse models; Janssen, CA, for providing the anti-VISTA antibody; and C.G. Liu of the Sequencing & Non-Coding RNA Program for microarray studies. The clinical trial was supported by Bristol-Myers-Squibb (BMS). The research work was also supported by funding from the American Association for Cancer Research (AACR) Stand Up To Cancer–Cancer Research Institute Cancer Immunology Dream Team Translational Research Grant (SU2C-AACR-DT1012; J.P.A., P.S., S.K.S., J.G.); the Prostate Cancer Foundation (PCF) Challenge Grant in Immunology (J.P.A., P.S.); a PCF 2014 Young Investigator Award (S.K.S.); a Conquer Cancer Foundation–American Society of Clinical Oncology (ASCO) 2012 Young Investigator Award (J.G.); Cancer Prevention Research in Texas (CPRIT) RP120108 (P.S.); NIH/NCI R01 CA1633793 (P.S.); and NIH/NCI K12 CA088084 (J.G.) and NIH/NCI P30CA016672 (MD Anderson Cancer Center institutional grant); NIH/NCI P50 CA140388 Prostate Cancer SPORE (P.S., J.P.A., S.K.S., C.J.L., E.E.).

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P.S. designed the study; L.Z.S., J.B., L.M.V., J.C., I.I.W., M.A.S., J.S., and H.C. performed the experiments; J.G., J.F.W., C.A.P., L.Z.S., J.C., J.B., L.M.V., I.I.W., J.S., H.Z., J.W., E.E., and P.T. analyzed the data; J.G., P.S., J.P.A., S.K.S., J.W., and C.J.L. drafted the manuscript; and all authors reviewed the final draft of the manuscript.

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Correspondence to Padmanee Sharma.

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Competing interests

P.S. and J.P.A. are founders and advisors for Jounce Therapeutics. P.S. and J.P.A. are members of the Parker Institute for Cancer Immunotherapy. P.S. also serves as a consultant for BMS, AstraZeneca, Amgen, and GlaxoSmithKline. J.P.A. is an inventor of intellectual property owned by the University of California, Berkeley, and licensed to BMS and has received royalties from BMS. J.P.A. is also inventor of intellectual property owned by Memorial Sloan Kettering Cancer Center and licensed to Merck. J.G. serves as a consultant for Genentech. I.I.W. serves as a consultant for BMS. E.E. serves as a consultant for Janssen, Bayer, Medivation, Astellas, and Sanofi Takeda.

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Gao, J., Ward, J., Pettaway, C. et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23, 551–555 (2017). https://doi.org/10.1038/nm.4308

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