# Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $370,575

## Abstract

Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy
 of PARP inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of ovarian cancer, as
well as BRCA1 or BRCA2 (BRCA1/2) mutant breast and pancreatic cancers. Our current understanding is that
one of the main mechanisms responsible for the efficacy of PARPis is through synthetic lethality, specifically in
cancers with homologous recombination repair defects (‘BRCAness’). While PARP1-mediated PARylation is
an essential regulator of gene transcription, it remains unknown how PARPi-induced transcriptomic changes
contribute to its therapeutic efficacy. While our preclinical and clinical studies assessing PARPis in combination
with programmed cell death-ligand 1 (PD-L1)/PD-1 inhibitors (PD-1/L1is) showed durable responses in
different cancers, the responses were heterogeneous between patients, and surprisingly, the therapeutic
benefit of this combination did not correlate with known predictive biomarkers for PARPis, such as BRCA1/2
mutations. These data suggest that the immunomodulating function of PARPis may be different from or
independent of the existing ‘BRCAness’ paradigm underlying the therapeutic efficacy of PARPis.
To determine the molecular mechanisms underlying the immunomodulating function of PARPis, we utilized
single-cell RNA sequencing to assess the transcriptomic impact of PARPis on tumor cells and the tumor
immune microenvironment. Surprisingly, we identified that PARPi-induced PARP1-trapping to DNA may
upregulate B7-H3 (CD276), a key immune checkpoint protein. Based on our preliminary studies, we
hypothesize that PARPis transcriptionally regulate cancer-cell intrinsic B7-H3 expression by trapping the
PARP1 protein to the B7-H3 promoter region, which may serve as a key regulatory node for the
immunomodulating function and therapeutic efficacy of PARPis. We will use cell and animal models, as well as
patient specimens from clinical trials of PARPi-based therapies to test this hypothesis. We will test three aims:
Aim 1: Determine mechanisms by which PARPis transcriptionally induce cancer cell intrinsic B7-H3
expression through PARP1-chromatin trapping. Aim 2: Determine if B7-H3 functions as a key regulatory node
for the immunomodulating function and efficacy of PARPis in preclinical animal models. Aim 3: Validate
PARPi-induced B7-H3 expression as a biomarker in determining the efficacy of PARPis as immunomodulating
agents by analysing patient tumor and blood samples from multiple clinical trials. We believe that our proposal
is highly innovative because it fills key gaps in our knowledge of the therapeutic efficacy of PARPis as
immunomodulating agents through transcriptional regulation, which goes beyond the current mechanistic
paradigm of PARPis. If successful, our study will have a significant impact on expanding the clinical
applications of PARPis as immunomodulating agents by promoting antitumor immunit...

## Key facts

- **NIH application ID:** 10095875
- **Project number:** 1R01CA255074-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Timothy Anthony Yap
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,575
- **Award type:** 1
- **Project period:** 2021-08-10 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095875

## Citation

> US National Institutes of Health, RePORTER application 10095875, Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors (1R01CA255074-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10095875. Licensed CC0.

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