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 antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor 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. We found that olaparib enhanced T1IFN production after radiation and had superior therapeutic efficacy in immunocompetent 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, single-cell RNA sequencing analysis revealed that combination treatment induced an immunogenic tumor microenvironment characterized by interferon (IFN) responses in both PDAC and myeloid cell populations, macrophage polarization, and increased CD8+ terminal effector T-cell frequency and activity, findings which were 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. See related commentary by Buchsbaum, p. 840.