Protective anti-tumor immunity is impaired by immunosuppressive mechanisms. Immune checkpoint proteins, including CTLA-4, PD-1, and B7-H4, function as effector molecules to disable T-cell responses against cancer. Although checkpoint blockade using monoclonal antibodies (mab) have shown positive outcomes in clinical trials, the overall response rate has been disappointingly as low as 6-21%. Therefore, identifying novel checkpoint proteins is critically needed. We have discovered and functionally characterized a new Ig-superfamily inhibitory ligand, designated V-domain Immunoglobulin Suppressor of T cell Activation (VISTA). We hypothesize that VISTA functions as an additional and crucial immune-checkpoint ligand that controls anti-tumor immunity. The goal in this grant proposal is to determine the molecular and cellular mechanisms of VISTA-mediated immune suppression, both via its direct effect on T effector cell activation, and via its regulatory functon on other immunosuppressive cell types, which in turn control T effector cell responses against cancer. Accordingly, the specific Aims are: (1) Determine the molecular mechanisms whereby VISTA suppresses T-cell activation, and how it collaborates with another immune-checkpoint pathway PD-L1/PD-1 to suppress tumor-specific T-cell responses. (2) Determine the role of VISTA on the development and function of Foxp3+CD4+ Tregs. (3) Define the role of VISTA on the development, differentiation, and function of mononuclear phagocytes in the normal physiological state and during tumorigenesis. A collection of novel reagents and models including VISTA mab, VISTAKO mice, and VISTA conditional KO mice will be used for this study. In addition to a transplantable melanoma B16F10 model, we will employ a clinically relevant inducible-melanoma model for mechanistic studies and assessing VISTA-based therapeutic strategies. Impact: Any successful cancer immunotherapeutic strategy must consider the negative immune regulators that prevent the development of optimal anti-tumor immunity. As a novel immune checkpoint pathway, VISTA provides a new target for the immune intervention in cancer. This study will provide answers regarding VISTA- mediated immune regulation during tumorigenesis. It will establish a novel paradigm in which VISTA and PD- L1/PD1 synergize to control T-cell responses, thus providing a rationale for targeting VISTA either alone or in combination with other immune checkpoint pathways for cancer immunotherapy. Further, this study will establish a new paradigm regarding how tumors utilize VISTA to alter the differentiation and functions of Tregs and monocytes, thus providing novel strategies for targeting these prominent immune-suppressors in cancer immunotherapy.
VISTA is a novel immune checkpoint protein that plays a critical and non-redundant role in tumor-induced immune suppression. VISTA blockade unleashes potent anti-tumor immunity. This study will define the molecular and cellular mechanisms of VISTA- dependent immunosuppressive pathways, and build a foundation for designing novel cancer immunotherapeutic strategies that targets VISTA.
|Xu, Wenwen; Hi?u, T?Minh; Malarkannan, Subramaniam et al. (2018) The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 15:438-446|
|Nanbakhsh, Arash; Best, Brad; Riese, Matthew et al. (2018) Dextran Enhances the Lentiviral Transduction Efficiency of Murine and Human Primary NK Cells. J Vis Exp :|
|Ceeraz, Sabrina; Eszterhas, Susan K; Sergent, Petra A et al. (2017) VISTA deficiency attenuates antibody-induced arthritis and alters macrophage gene expression in response to simulated immune complexes. Arthritis Res Ther 19:270|
|Li, Na; Xu, Wenwen; Yuan, Ying et al. (2017) Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 7:1485|
|Rajasekaran, Kamalakannan; Riese, Matthew J; Rao, Sridhar et al. (2016) Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy. Front Immunol 7:176|
|Green, Kathy A; Wang, Li; Noelle, Randolph J et al. (2015) Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus. J Virol 89:9693-8|
|Liu, Jun; Yuan, Ying; Chen, Wenna et al. (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 112:6682-7|
|Imai, Yasutomo; Ayithan, Natarajan; Wu, Xuesong et al. (2015) Cutting Edge: PD-1 Regulates Imiquimod-Induced Psoriasiform Dermatitis through Inhibition of IL-17A Expression by Innate ??-Low T Cells. J Immunol 195:421-5|
|Lines, J Louise; Sempere, Lorenzo F; Broughton, Thomas et al. (2014) VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2:510-7|
|Wang, Yan; Telesford, Kiel M; Ochoa-Repáraz, Javier et al. (2014) An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun 5:4432|
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