# Targeting dsRNA sensing and ADAR1 in melanoma

> **NIH NIH R37** · YALE UNIVERSITY · 2024 · $631,778

## Abstract

PROJECT SUMMARY:
Over the past decade the development of immune checkpoint blockade (ICB) in melanoma and other tumor
types has transformed the treatment options available for many patients with cancer. However, within
melanoma only approximately half of patients experience a durable response to treatment, with worse results
in most other tumor types. We and others have identified strategies to enhance anti-tumor immunity and
sensitize non-responsive murine melanoma tumors to ICB by targeting dsRNA pattern recognition receptors
(PRRs). These strategies include the agonism of the dsRNA sensor RIG-I and the loss of Adenosine
Deaminase Acting on dsRNA (ADAR1). We showed that ADAR1 is an innate inhibitory checkpoint in tumor
cells that limits anti-cancer immunity, and that targeting it therapeutically can trigger multiple dsRNA PRRs to
sensitize tumors to immunotherapy. Both RIG-I agonism and targeting ADAR1 resulted in enhanced cytokine
release in murine tumor microenvironments and improved the recruitment and control of tumors by T cells. In
recent work we have uncovered evidence that co-targeting multiple dsRNA sensing pathways induces
cooperative effects and enhances anti-tumor immunity compared with targeting single sensors. However,
several gaps in knowledge limit the translation of these strategies into effective therapies for patients. These
include: i) defining the optimal therapeutic strategy for targeting dsRNA PRRs; ii) understanding mechanisms
by which dsRNA sensing in tumors programs immune cell function; and iii) identifying the patients most likely
to respond to dsRNA-targeting therapeutics. To test the effects of dsRNA PRR stimulation on patient tumor
and immune samples ex vivo, we developed a novel perturbational single cell RNA sequencing approach.
Applying this strategy, we found that dsRNA stimulation of patient tumor and immune cells induces distinct T
cell programs of activation and survival and that these approaches may be most effective in tumors with high
pre-treatment levels of interferon signaling and adenosine-to-inosine dsRNA editing. In Aim 1 of this proposal,
we will test the hypothesis that co-targeting ADAR1 and RIG-I enhances the activation, proliferation and
function of anti-tumor T cells. We will explore mechanisms of this finding in mouse models including the
increased recruitment, activation and cross-presentation of tumor antigens by dendritic cells. In Aim 2 we will
seek to identify the tumor determinants of therapeutic response to targeting ADAR1 and uncover insights that
will facilitate the development of small molecule and nucleic acid therapeutics. If successful, the work
described in this proposal will help define the rules by which tumors and T cells respond to dsRNA stimulation
and advance the development of dsRNA-targeting strategies for melanoma and other tumors.

## Key facts

- **NIH application ID:** 10803352
- **Project number:** 1R37CA279834-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jeffrey J. Ishizuka
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $631,778
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803352

## Citation

> US National Institutes of Health, RePORTER application 10803352, Targeting dsRNA sensing and ADAR1 in melanoma (1R37CA279834-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10803352. Licensed CC0.

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