# Delineating how nucleic acid sensing in tumorcells regulate anti-tumor immune responses

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $360,545

## Abstract

Project Summary
Impaired DNA damage responses can lead to genomic and chromosomal instability in cancer. High levels of
chromosomal instability have been associated with increased mutation rates, metastasis, and immune evasion
in cancer. Paradoxically however, DNA- damaging chemo- and radio-therapies can trigger anti-tumor
inflammatory responses. How DNA damage in tumor cells regulate both anti-and pro-tumor immune responses
within the tumor microenvironment (TME) represents an important knowledge gap. The Greenberg group
(Project 1) has shown that DNA damage in cancer cells activate cytosolic DNA sensing pathway regulated by
cyclic AMP-GMP synthase (cGAS) and stimulator of interferon genes (STING), as well as an RNA sensing
pathway regulated by retinoic acid-inducible gene I (RIG-I). Activation of these nucleic acid-sensing pattern
recognition receptors (PRRs) induces type I interferon (IFN-I) – a cytokine that promotes protective immunity
against pathogens. Cytosolic nucleic acids can also activate inflammasomes to secrete interleukin (IL)-1β and -
18, which have both pro- and anti-tumor effects. Intriguingly, our preliminary data suggest that inflammasome
activation in response to DNA damage promotes tumor growth in an ovarian cancer model. Antigen presenting
cells (APCs) are key mediators of immune responses and our recent work have identified novel subsets of APCs
and their regulation by interferons in the TME. In this proposal, we will examine the hypothesis that the outcome
of tumor control is driven by the opposing anti- and pro-tumor effects of IFN-I and IL-1β/ IL-18 on APCs in
response to cancer cell DNA damage. Towards this goal, we will closely collaborate with Projects 1 (Greenberg)
and 2 (Lampson/Discher) and rely on novel genetic (MAC core) and chemical (Chemical Biology Core) tools.
The three specific aims will examine the mechanisms underlying IFN-I-dependent anti-tumor (Aim 1) and
inflammasome dependent pro-tumor (Aim 2) effects of cancer cell DNA damage, and provide proof-of-concept
for targeting these pathways for combinatorial immunotherapy (Aim 3). These findings will provide fundamental
insights into immune mechanisms underlying how genome instability regulates immune responses in tumor and
provide a foundation for future attempts to target these pathways for cancer therapy.

## Key facts

- **NIH application ID:** 10838540
- **Project number:** 5P01CA265794-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Malay Haldar
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,545
- **Award type:** 5
- **Project period:** 2023-05-08 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838540

## Citation

> US National Institutes of Health, RePORTER application 10838540, Delineating how nucleic acid sensing in tumorcells regulate anti-tumor immune responses (5P01CA265794-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10838540. Licensed CC0.

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