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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA164225-08
Application #
9974483
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Kuo, Lillian S
Project Start
2012-09-01
Project End
2024-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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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