# Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $570,047

## Abstract

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 predict...

## Key facts

- **NIH application ID:** 10170281
- **Project number:** 5R01CA214062-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** RANDOLPH J. NOELLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,047
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170281

## Citation

> US National Institutes of Health, RePORTER application 10170281, Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors (5R01CA214062-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170281. Licensed CC0.

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