# Dissecting the influence of DNA damage response and homologous recombination deficiencies on tumor immunogenicity

> **NIH NIH DP5** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $423,750

## Abstract

Project Summary
With the rapid expansion of the use of immune checkpoint inhibitors (ICI) across a wide variety of histologies, it
remains clear that only small minorities of patients respond. There is therefore a large need for improved
predictors of response to immunotherapy. In particular, in cancers associated with germline defects in
homologous recombination, including breast, ovarian, and prostate cancer, response rates to immunotherapy
have been very low in large phase 3 trials, in some cases leading to a decision by pharmaceutical companies
to no longer pursue FDA approval for these indications. DNA-repair deficiency could serve as a useful and
clinically relevant biomarker to select appropriate patients for immunotherapy. This is reminiscent of the recent
FDA approval of pembrolizumab for patients with mismatch repair deficient tumors regardless of histology. A
similar concept may extend to other defects in DNA-damage response and repair (DDR) pathways, the most
common being homologous recombination (HR). Defects in homologous recombination repair have been
studied extensively due to the hereditary predisposition for breast, ovarian prostate, and pancreatic cancer with
mutations in important HR genes BRCA1 and BRCA2. More recently, phenotypic determination of homologous
recombination deficiency (HRD) using genomic correlates have estimated up to 30% of breast and ovarian
cancers may be HRD as well as a small portion of many other histologies. In ongoing work we have implicated
mutations in the homologous recombination pathway with improved survival after ICI in a large retrospective
cohort. However, divergent responses were noted depending on the HR gene mutated. This proposal aims to
further explore the hypothesis that HRD and other DDR defects result in increased immunogenicity and as a
result improved response to immunotherapy and elucidate the mechanisms involved in resulting immune
recognition and response to ICI.
Aim 1 will focus on gaining an understanding of which genes are associated with response to ICI and explain
the divergent responses observed clinically. A thorough analysis of the immune microenvironment will result in
important insights regarding which patients my benefit and why.
Aim 2 will attempt to elucidate what components of the immune system are directly influenced by HRD and
DDR deficiencies focusing on innate immunity pathways.
Aim 3 will study the effects of other DDR pathway deficiencies or activation using drugs or radiation and their
affects on response to ICI, exploring potential synergy.

## Key facts

- **NIH application ID:** 10247628
- **Project number:** 5DP5OD028171-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Robert M Samstein
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2019-09-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247628

## Citation

> US National Institutes of Health, RePORTER application 10247628, Dissecting the influence of DNA damage response and homologous recombination deficiencies on tumor immunogenicity (5DP5OD028171-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247628. Licensed CC0.

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