Abstract A070: Olaparib enhances radiation-induced Type I interferon and sensitizes pancreatic cancer to PD-L1 immune checkpoint inhibition

Abstract

Abstract Inhibitors of PARP have been shown to sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation therapy through mechanisms involving DNA damage, replication stress, and PARP trapping independent of BRCA1/2 mutation status. These mechanisms have the potential to activate innate immune signaling leading to Type I Interferon (T1IFN) production. Thus, we hypothesized that the clinical PARP1/2 inhibitor olaparib would potentiate radiation-induced T1IFN to activate an anti-tumoral immune response and sensitize resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and signaling, tumor growth, sensitivity to PD-L1 immunotherapy, and the tumor immune microenvironment in mouse models of PDAC. We found that clinically achievable concentrations of olaparib significantly enhanced radiation-induced T1IFN production measured by both an IFNβ promoter-driven reporter and Ifnβ mRNA levels. Additionally, we found that the downstream effects of radiation-induced T1IFN signaling, including PD-L1 and MHC-I cell surface expression and induction of interferon stimulated genes including Cxcl9 and Cxcl10, were enhanced by olaparib. Co-treatment with a T1IFN receptor blocking antibody diminished these effects supporting the requirement for T1IFN-dependent signaling for the innate immune effects of radiation and olaparib. In vivo treatment with olaparib and radiation sensitized tumors to anti-PD-L1 therapy with a 40% complete response rate. These therapeutic responses led to an adaptive long term immunogenic memory evidenced by reduced engraftment following tumor rechallenge. Single-cell RNA sequencing revealed that treatment with olaparib, radiation and anti-PD-L1 augmented an anti-tumoral CD8+ T cell immune response, which is supported by an increase in CD8+ effector T cells and a decrease in CD8+ dysfunctional T cells. The necessity of functional CD8+ T cells to therapy efficacy in vivo was further reflected by a significantly reduced therapeutic combinational efficacy using a CD8+ T cell blocking antibody. Taken together, the results of this study show that the combination of olaparib, radiation and anti-PD-L1 induce an anti-tumoral immune response mediated by both T1IFN and CD8+ T cells. The results of this study provide the rationale for a phase 1 clinical trial (NCT05411094) combining dose escalated olaparib with durvalumab and radiotherapy in patients with locally advanced pancreatic cancer. Citation Format: Victoria M Valvo, Qiang Zhang, Long Jiang, Ashkay Tate, Michael D Green, Meredith A Morgan. Olaparib enhances radiation-induced Type I interferon and sensitizes pancreatic cancer to PD-L1 immune checkpoint inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A070.