Immune-checkpoint receptors such as CTLA-4 and PD-1 have been successfully targeted for cancer immunotherapy. Our earlier work has identified V domain Immunoglobulin Suppressor of T cell Activation (VISTA) as an immune-checkpoint protein that critically regulates anti-tumor immunity. Despite this progress, how VISTA inhibits T cell activation is not understood. Our current study has identified a novel VISTA-interacting receptor that is expressed on murine and human T cells and mediates the suppressive effect of VISTA. The overarching goals of this proposal are to define the cellular and molecular mechanisms of this novel T cell coinhibitory complex.
Specific aim 1 will dissect the interactions between VISTA and its receptor and establish the relevance of ubiquitin-modifying enzymes to the inhibitory signaling.
Aim 2 will examine the role of VISTA and its receptor in regulating tumor-specific T cell responses, utilizing a newly generated conditional knockout mice and novel inhibitors that block this inhibitory receptor complex. The protein expression level of VISTA and its receptor in human cancer tissues will also be examined. Together, these proposed studies will build a foundation for developing novel inhibitors that target the VISTA receptor complex for cancer immunotherapy.
V domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune-checkpoint ligand protein and a critical regulator of anti-tumor immunity. Our current study has identified a novel VISTA-interacting receptor. This proposal will define the cellular and molecular mechanisms by which VISTA and its receptor regulate tumor-specific T cell responses and develop therapeutic reagents that block this inhibitory pathway for cancer therapy.
|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|
|Le Mercier, Isabelle; Chen, Wenna; Lines, Janet L et al. (2014) VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 74:1933-44|
|Wang, Li; Le Mercier, Isabelle; Putra, Juan et al. (2014) Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity. Proc Natl Acad Sci U S A 111:14846-51|
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