IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma Rahul Mirlekar1,2, Yuliya Pylayeva-Gupta1,2,* 1Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599; 2Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina *Correspondence 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. 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 PDAC growth. This correlates with induction of immunosuppressive regulatory T cells and suppression of effector T cell activity, suggesting that IL-35 controls endogenous anti-tumor 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 anti-tumor 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-PD1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDAC may be expeditiously translated into IL-35 targeted combination immunotherapy.
Credits: None available.
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