Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer

Authors

Victoria M Valvo
Qiang Zhang
Long Jiang
Erin A Holcomb
Ashley N Pearson
Anna G Edmunds
Hailey G Faulkner
Jadyn G James
Akshay Tate
Amanda K Huber
Zhuwen Wang
Yupei Guo
David Karnak
Leslie A Parsels
Joshua D Parsels
Yu L Lei
Alnawaz Rehemtulla
Heng Lin
Eileen S Carpenter
Daniel R Wahl
Vaibhav Sahai
Theodore S Lawrence
Michael D Green
Meredith A Morgan

Publication Date

6-4-2025

Journal

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-24-0210

PMID

39688341

PMCID

PMC12137021

PubMedCentral® Posted Date

12-4-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN) mediated anti-tumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote anti-tumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). We found that olaparib enhanced T1IFN production following radiation and had superior therapeutic efficacy in immune competent models. Olaparib and radiation treatment sensitized PDAC tumors to αPD-L1 resulting in decreased tumor burden and a 33% complete response rate. Combination treatment provided durable immune responses as shown by tumor rejection upon tumor rechallenge of previously cured mice. Furthermore, scRNA-seq analysis revealed that combination treatment induced an immunogenic tumor microenvironment, characterized by interferon responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T cell frequency and activity, findings confirmed by IHC and flow cytometry. Furthermore, CD8+ T cells and T1IFN signaling were required for therapeutic efficacy as host depletion of CD8+ T cells or the T1IFN receptor diminished treatment responses. Overall, our results indicate that olaparib enhances radiation-induced T1IFN-mediated immune signaling and subsequently an adaptive immune response thus sensitizing pancreatic cancer to αPD-L1 therapy, supporting an ongoing clinical trial of this therapy in patients with PDAC.

Keywords

Animals, Phthalazines, Piperazines, CD8-Positive T-Lymphocytes, Interferon Type I, Mice, Humans, Pancreatic Neoplasms, Immunotherapy, Cell Line, Tumor, Tumor Microenvironment, Disease Models, Animal, Xenograft Model Antitumor Assays, Carcinoma, Pancreatic Ductal, DNA damage response, interferon, immune checkpoint, tumor immune microenvironment

Published Open-Access

yes

Recommended Citation

Valvo, Victoria M; Zhang, Qiang; Jiang, Long; et al., "Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer" (2025). Faculty, Staff and Student Publications. 5768.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5768