PARP7 inhibition combined with radiotherapy to overcome ICI resistance in breast cancer

The National Cancer Institute awarded the University of North Carolina at Chapel Hill $100,228 on December 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research into PARP7 inhibition combined with radiotherapy to overcome immune checkpoint inhibition resistance in triple negative breast cancer.

The funded work characterizes mechanisms by which PARP7 inhibition augments the synergy between radiotherapy and immune checkpoint inhibition in preclinical murine tumor models. Aim 1 employs syngeneic murine tumor models and flow cytometry to analyze T cell states under combinatory treatment, with in vitro co-culture assays to assess how PARP7 inhibition impacts CD8+ T cell cytotoxic activity and dendritic cell antigen cross-presentation. Aim 2 applies bulk and single-cell RNA-sequencing to generate gene expression signatures predictive of radiotherapy and immune checkpoint inhibition responsiveness. The research addresses the clinical challenge that radiotherapy and immune checkpoint inhibition synergy is not observed uniformly across triple negative breast cancer tumors and that systemic anti-tumor abscopal responses occur infrequently despite preliminary data showing PARP7 inhibition enhances interferon-stimulated gene induction and systemic anti-tumor immune responses in preclinical models.

Performance occurs in Chapel Hill, North Carolina, with period of performance extending through June 30, 2029. The Cancer Research Manpower program supports biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research relevant to the National Cancer Program.

Abstract

Breast cancer is the most commonly diagnosed cancer in the world, with the triple negative subtype (TNBC) having the worst overall survival and least treatment options. The standard of care for TNBC remains surgical resection, neoadjuvant chemotherapy, radiation (RT), and immune checkpoint inhibition (ICI). While ICI is becoming a widely used therapeutic in many cancer types, IT is inefficient as a monotherapy in TNBC and concurrently given with chemotherapy. RT has been suggested as a way to boost immune activation in combination with ICI, which is being investigated in a clinical trial through the gupta lab (NCT04443348). However, RT/ICI synergy is not observed in all tumors and the induction of systemic anti-tumor (i.e., "abscopal") responses are relatively infrequent. The goal of this study is to identify targetable pathways that may guide patient selection and augment RT/ICI synergy by screening a panel of clinically representative breast cancer immune-competent mouse models. Preliminary data in the lab has identified the mono-ADP- ribosyltransferase PARP7 as a biomarker of RT/ICI responsiveness that, when inhibited, results in significantly greater induction of interferon-stimulated genes (ISGS) and systemic anti-tumor immune responses in preclinical murine models. The mechanism through which PARP7I overcomes RT/ICI resistance remains unclear. In aim 1, I will use syngeneic murine tumor models to characterize PARP7-mediated RT/ICI resistance in a known tumor antigen model. Using a comprehensive flow cytometry panel, I will analyze T cell states with combinatory treatment. Through in vitro CO-culture assays, I aim to characterize how PARP7I impacts the cytotoxic activity of CD8+ T cells and antigen cross presentation through dendritic cells. In aim 2, I will use bulk and single cell (SC)RNA-sequencing of syngeneic murine tumor models to create a gene expression signature of PARP7-mediated RT/ICI resistance and assess the immune cell specific effect of PARP7I. Using RNA-sequencing data from the P-RAD clinical trial being investigated in our lab (NCT04443348), I aim to evaluate the gene expression signature generated to predict RT/ICI response in the clinical cohort, and as a predictor of major pathological response to RT/ICI. Both bulk and SC/snrna-SEQ aim to provide a signature for RT/ICI resistant tumors that may benefit from PARP7I. Together, these studies will use mouse and human data to characterize the mechanism by which PARP7I overcomes RT/ICI resistance and define a gene expression signature to predict clinical response, which may lead to novel therapeutic options to improve patient outcomes.