# An innate immune checkpoint in cancer immunotherapy

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $527,107

## Abstract

Cancer immunotherapy attempts to boost the body’s own defense mechanism – the immune system – to kill
cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize
cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of
patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of
positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may
correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor
immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular
protein named MERTK, that is found in innate immune cells – the body’s first line of immune defense. MERTK
limits the extent to which innate immune cells can get activated, which in turn controls how much the overall
immune response would be. We have also detected the presence of MERTK in tumor-associated innate
immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic
prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s
by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in
established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti-
tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK
activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better
understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of-
concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for
the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our
proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in
combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly
increase the percentage of patients that show objective response to anti-cancer therapy.

## Key facts

- **NIH application ID:** 9858312
- **Project number:** 5R01CA212376-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sourav Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $527,107
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858312

## Citation

> US National Institutes of Health, RePORTER application 9858312, An innate immune checkpoint in cancer immunotherapy (5R01CA212376-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858312. Licensed CC0.

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