# Tumor cell instrinsic DNA damage signaling to the immune response

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $346,239

## Abstract

Summary
The efficacy of DNA damaging cancer therapies is determined by the (i) intrinsic DNA repair
capacity of cancer cells, and (ii) immune responses to signals emanating from tumors.
Understanding the molecular basis of communication between the DNA damage and immune
responses is therefore a central issue to both cancer etiology and therapy. We reported that
mitotic progression after DNA damage allows cGAS-STING dependent pattern recognition of
DNA in micronuclei to initiate interferon-stimulated gene expression and T-cell dependent
eradication of distant metastases. Disruption of DNA damage induced cell cycle checkpoints
together with p53 mutation resulted in pattern recognition receptor responses by both DNA and
RNA sensors, including the cGAS-STING and the MDA5 and RIG-I/MAVs pathways. Our
unpublished findings reveal additional complexity to these responses. NLRP9 inflammasome
assembly is increased in chromosomally instable cancer cells and opposes interferon stimulated
responses. Interestingly, NLRP9 deficiency delayed tumor formation in a murine Brca2 mutant
high grade serous ovarian cancer model commensurate with reversal of an immune
suppressive tumor microenvironment. These findings potentially explain how DNA damage can
either activate or suppress anti-tumor immune responses.
This proposal will take cellular, biochemical, and in vivo approaches to test hypotheses that
chromosome instability activates dichotomous inflammatory signaling responses that
differentially affect tumor growth. The importance of these mechanisms to cancer
immunotherapy will be tested in syngeneic tumor models that assess systemic anti-tumor
immune responses to combinations of DNA damaging therapies and immune checkpoint
blockade. Collaborations with Projects 2 and 3, and with the Mammalian Artificial Chromosome
and Chemical Biology Cores will be instrumental to these studies.

## Key facts

- **NIH application ID:** 10838531
- **Project number:** 5P01CA265794-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Roger A Greenberg
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $346,239
- **Award type:** 5
- **Project period:** 2023-05-08 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838531

## Citation

> US National Institutes of Health, RePORTER application 10838531, Tumor cell instrinsic DNA damage signaling to the immune response (5P01CA265794-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10838531. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*