# Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy

> **NIH NIH F99** · YALE UNIVERSITY · 2020 · $36,062

## Abstract

PROJECT SUMMARY
Immune-modulating therapies have been revolutionary treatments for several cancer types including melanoma,
lung cancer, and renal cell carcinoma. However, most cancer patients do not respond to immunotherapies, and
there remains a critical need to identify alternative approaches to treating these cancers. Endogenous
retroviruses (ERVs) are genetic remnants of retroviral infection transmitted vertically through generations, whose
transcription can result in type-I interferon activation, and/or presentation of ERV-associated antigens. Recent
studies on ERVs in human cancer has shown that ERV expression can render cells immunogenic in a variety of
cancer types including colorectal, breast cancer and melanoma. Therefore, characterization of how ERV
expression is regulated in cancer will reveal opportunities to therapeutically de-repress ERVs and improve
immunotherapy outcomes in low antigen tumors.
In the F99-phase of this proposal, I will investigate the role of epigenetic factors regulating ERV expression and
anti-tumor immunity in melanoma. Specifically, I will test melanoma tumors for ERV tetramer-positive CD8+ T
cells, to determine the antigenicity of de-repressed melanoma ERVs. Furthermore, I will determine the
mechanism by which type-I interferon response is induced in epigenetically-modified tumors, and determine the
role of ERV MHC-I antigens through genetic knockouts of each component and evaluating tumor growth and
immunogenicity. This work will establish the mechanism by which ERVs are regulated epigenetically, and
establish a framework for investigating ERV regulation and its impact on the immune response to cancer.
In the K00-phase of this proposal, I will harness my experience studying ERVs to investigate their utility in
improving the immune response to antigen-low tumor types. Specifically, I will perform a CRISPR screen to
identify druggable regulators of HERV expression in human cancer cell lines. I will then validate these candidate
regulators by pharmacologically targeting them and testing the induction of type-I interferon and antigenic
responses in these cells. Finally, I will evaluate whether ERV-specific CAR-T cells can react to ERV-induced
cells in vivo.
This proposed research will clarify the mechanisms by which ERVs are epigenetically regulated in cancer, and
identify novel and actionable targets for re-expressing ERVs in difficult-to-treat tumor types. This will lead to
improved immunotherapeutic strategies for treating cancers with poor patient outcomes.

## Key facts

- **NIH application ID:** 10065210
- **Project number:** 1F99CA253767-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Meaghan K. Van Den Eynde
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,062
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065210

## Citation

> US National Institutes of Health, RePORTER application 10065210, Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy (1F99CA253767-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065210. Licensed CC0.

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