Olaparib and radiotherapy induce type I interferon and CD8+ T cell-dependent sensitization to immunotherapy in pancreatic cancer
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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 consequent effects 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. Treatment with olaparib and radiation 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. 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. Taken together, 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.
ORGANISM(S): Mus musculus
PROVIDER: GSE276238 | GEO | 2024/12/01
REPOSITORIES: GEO
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