Abstract 4674: IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma

Abstract

Abstract Despite advances in our understanding of the mutational landscape in pancreatic ductal adenocarcinoma (PDA), this devastating disease is now the third-leading cause of U.S. cancer-related deaths. While recent successes of cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic cancer. A major barrier for immunotherapeutic approaches is marked immunosuppression within the PDA milieu. We have previously identified a novel role for IL-35 producing B regulatory cells in the pathogenesis of pancreatic cancer. However, little is known about the mechanisms behind IL-35 activity in cancer. The overarching goal of this project is to elucidate molecular and cellular mechanisms by which IL-35 facilitates the emergence of pancreatic cancer. Our results demonstrate that IL-35, but not IL-10, potentiates PDA growth. This correlates with induction of immunosuppressive T regulatory cells (Treg) and suppression of T effector cell (Teff) and cytotoxic CD8+ T cell activity, suggesting that IL-35 controls anti-tumor immune responses in PDA. Remarkably, while PDA is typically resistant to anti-PD1 immunotherapy, IL-35 deficiency converted PDA from immunologically ‘cold' to ‘hot' tumor, which allowed for a robust synergistic reduction in tumor growth in response to anti-PD-1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDA may be expeditiously translated into IL-35 targeted combination immunotherapy. Citation Format: Bhalchandra Mirlekar, Ryan Searcy, Yuliya Pylayeva-Gupta. IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4674.