Abstract PR21: IL-35+ B cells establish immunosuppressive network in pancreatic ductal adenocarcinoma

Abstract

Abstract Despite advances in our understanding of the mutational landscape in pancreatic ductal adenocarcinoma (PDAC), 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 PDAC milieu. We have previously identified a novel role for IL-35-producing B cells in the pathogenesis of pancreatic cancer. However, little is known about the mechanisms behind IL-35 activity in cancer. Here, we set out 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 PDAC growth. This correlates with induction of regulatory T cells and suppression of effector T-cell activity, suggesting that IL-35 controls endogenous antitumor immune responses in PDAC. Furthermore, while IL-35 is expressed by several immune cell types in PDAC, we show that its expression specifically in B cells is essential for suppression of antitumor T-cell responses. Importantly, while PDAC is typically resistant to anti-PD-1 immunotherapy, we demonstrate robust synergistic reduction in tumor growth when IL-35 deficiency is combined with anti-PD-1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDAC may be expeditiously translated into IL-35 targeted combination immunotherapy. This abstract is also being presented as Poster A28. Citation Format: Bhalchandra Mirlekar, Yuliya Pylayeva-Gupta. IL-35+ B cells establish immunosuppressive network in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR21.