V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir-/- mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir-/- CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity has not been demonstrated. Our current study shows that VISTA-blocking monoclonal antibody (mAb) enhanced anti-tumor T cell response, and synergized with a peptide vaccine and TLR7 agonist imiquimod as adjuvant to suppress tumor growth in the B16 melanoma model. Surprisingly, the therapeutic effect of this combination therapy was abolished in the IL17R knockout hosts, indicating that the IL-17-mediated inflammation is regulated by VISTA and is required for anti-tumor immunity in the context of VISTA blockade. To better define the regulatory role of VISTA in inflammation, we employed a murine model of psoriasis induced by topical treatment of IMQ. Our data show that VISTA deficiency exacerbated the psoriasiform inflammation. Enhanced TLR7 signaling in Vsir-/- dendritic cells (DCs) led to the hyper-activation of Erk1/2 signaling and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRgd+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27- gd T cells, and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27- gd T cells were expanded in the Vsir-/- mice and amplified the inflammatory cascade. Together, these results indicate that VISTA is a critical regulator of the IL-23/IL-17-mediated inflammatory axis. Ongoing studies will define how IL-17 regulates tumor-reactive immunity in the context of VISTA blockade and TLR vaccine adjuvant.

Citation Format: Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Samuel T. Hwang, Subramaniam Malarkannan, Li Wang. Immune checkpoint protein VISTA is a critical regulator of the IL-23/IL-17 inflammatory axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2017-4685

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.