# Targeting TIGIT and PD-1 in Melanoma

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $357,994

## Abstract

PROJECT SUMMARY/ABSTRACT
There is ample evidence that patients with melanoma can develop immune responses directed against
antigens expressed by their tumor. However, high tumor antigen (TA)-specific cytotoxic T cell (CTL)
frequencies often fail to induce melanoma rejection. Understanding the failure of TA-specific T cells to promote
tumor regression is, therefore, critical for the design of novel therapeutic interventions aimed at overcoming
tumor-induced immune escape. Among the numerous mechanisms of tumor-induced immunosuppression that
contribute to the resistance of tumors to CTLs, a number of studies in animals and humans have suggested
the role of inhibitory pathways in impeding CTL effector functions. TA-specific CD8+T cells in peripheral blood
lymphocytes (PBLs) or tumor-infiltrating lymphocytes (TILs) of patients with advanced melanoma upregulate
the expression of multiple inhibitory receptors (IRs), including PD1, Tim3, and TIGIT. We have previously
shown that these IRs interact with their ligands expressed in the tumor microenvironment to impede of TA-
specific CD8+ T cell expansion and functions in the context of chronic antigen stimulation. In particular, we
have shown for the first time that TIGIT blockade adds to PD-1 blockade to increase TA-specific CD8+T cell
functions in vitro. We have also reported that CD8+TILs in metastatic melanoma downregulate the
costimulatory receptor CD226, which competes with TIGIT for binding to the same ligands. Interestingly, TIGIT
is also upregulated by highly suppressive CD4+ regulatory T cells (Tregs). The mechanisms supporting the role
of TIGIT in regulating Tregs and CD8+T cells remains poorly understood. Based on novel findings, we propose
to investigate the mechanisms supporting the role of TIGIT and TIGIT/CD226 imbalance in regulating Tregs
and CD8+T cells, respectively, in melanoma. We will also investigate the role of CD226 in regulating anti-tumor
immune responses and tumor rejection upon dual PD-1/TIGIT blockade in vivo in mouse-bearing melanoma.
Finally, we will test the efficacy of novel Fc-engineered anti-mouse TIGIT antibodies to target Tregs or
CD8+TILs in vivo, and promote tumor rejection in combination with PD1 blockade. Collectively, the information
derived from the outlined studies will serve as a rationale for the development of novel therapeutic strategies to
reverse tumor-induced T cell dysfunction in patients with advanced melanoma and increase the likelihood of
clinical benefits.

## Key facts

- **NIH application ID:** 9938497
- **Project number:** 5R01CA228181-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** HASSANE M ZAROUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,994
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938497

## Citation

> US National Institutes of Health, RePORTER application 9938497, Targeting TIGIT and PD-1 in Melanoma (5R01CA228181-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938497. Licensed CC0.

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