Targeting VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) can eradicate large, established tumors that are resistant to PD-1/CTLA-4 blockade (?checkpoint-resistant? tumors). We propose this is because anti-VISTA can relieve T cell suppression and also reduce the myeloid-derived suppressor cell (MDSC) composition and function within the tumor microenvironment (TME). To our knowledge, there is no other antibody-based therapy that results in this outcome. Furthermore, data in human tumors are showing that high levels of VISTA expression in the TME is correlated with poor survival. The mission of this proposal is to define the mechanisms underlying the anti-VISTA pro-survival impact in established tumors. The emerging recognition that VISTA is functionally bi-directional, acting as both a ligand and a receptor and is expressed on multiple hematopoietic lineages (T cells, myeloid) opens up an expanding breadth of mechanisms that could account for its role in T cell suppression and MDSC function. We present VSIG8, another Ig supergene family member that we identified as the VISTA counter-receptor.
Specific Aim #1 tests two hypotheses that explain VISTA-mediated suppression. First, that VISTA, acting as a ligand expressed on APCs/MDSCs, triggers suppression of T cells through VSIG8. Second, VISTA expressed on T cells, acting as a receptor, when engaged by VSIG8 triggers T cell suppression. These are two distinct hypotheses that could account for the VISTA-mediated immune suppression in cancer. Their resolution will bring decisive new information on the mechanisms of anti-VISTA action in tumor immunotherapy.
Specific Aim #2 addresses yet another new fundamental role of VISTA as a receptor that controls MDSC function. We report that VISTA targeting results in a striking reduction of Ly6G+ MDSCs and tumor associated macrophages (TAMs) within the TME. Additional studies confirm a central and profound immunoregulatory role of VISTA in controlling MDSC biology (mediator production, chemotaxis, etc). We propose that the the pleiotropic effects of VISTA targeting of MDSCs impacts the immune status of the TME and is central to the elimination of ?checkpoint-resistant? tumors. All murine studies support the hypothesis that heightened VISTA expression within the TME will impair the development of tumor immunity. The evaluation of mRNA expression of VISTA in colorectal cancer patients revealed a strong correlation between heightened VISTA expression in the TME and shorter overall survival. This correlation was driven by granulocytic and monocytic cell infiltration.
In Specific Aim #3 we propose to greatly improve our resolution of VISTA expression in human and mouse colorectal cancer by combined genetic and imaging technologies to define the spatial distribution of VISTA in the TME and define in detail the intensity and distribution of VISTA on TME leukocyte subsets. We propose that these strategies will provide clear and decisive predictive biomarkers and guide the clinical development of anti-VISTA therapies that entered the clinic in January of 2016.

Public Health Relevance

. Targeting of immune negative checkpoint regulator (NCR) pathways is revolutionizing the treatment of human cancers and has established that these pathways are proven clinical targets in human disease. VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation), is a recently- identified, NCR ligand/receptor that is being developed as a target for human malignancies. Clinical trials with aVISTA antibodies have commenced. This proposal will define how VISTA controls the immune system to make protective immune responses to cancer and may help us to understand who will benefit the most from anti-VISTA therapy. Understanding how targeting this molecule cures cancer will provide guidance for future therapeutic applications in oncology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Howcroft, Thomas K
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Dartmouth College
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Molodtsov, Aleksey; Turk, Mary Jo (2018) Tissue Resident CD8 Memory T Cell Responses in Cancer and Autoimmunity. Front Immunol 9:2810
Shabaneh, Tamer B; Molodtsov, Aleksey K; Steinberg, Shannon M et al. (2018) Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis. Cancer Res 78:5038-5049