Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to therapy and has a dismal 5-year survival rate. Development of PDAC is accompanied by changes in stromal responses and immune surveillance programs, which are now recognized as major drivers of PDAC tumor evolution and contribute to therapeutic resistance. We have recently demonstrated that B cells expressing the immunomodulatory cytokine IL35 are necessary to support the growth of PDAC in murine models. The overarching goals of this proposal are to elucidate mechanisms underlying the tumor-promoting effect of IL35 expression in B cells, and to investigate the translational potential of targeting the IL35 pathway as a novel means to augment immunotherapy for this disease.
In Aim 1, we will define essential role for IL35 expressing B cells in establishing an immunosuppressive microenvironment in PDAC using B cell specific knockout of IL35 and chimeric bone marrow reconstitution.
In Aim 2, we will clarify how B cell receptor (BCR) and CD40 signaling contribute to induction of IL35 expression in tumor-reactive B cells. To accomplish this task, we will analyze mouse models expressing a fixed BCR with or without antigen exposure, as well as mouse models lacking CD40 signaling in B cells. We will also perform signaling pathway analysis in primary B cells and B cell lines.
In Aim 3, we will assess the translational potential of targeting pathogenic B cells in PDAC. Specifically, we will quantify, functionally characterize and study gene expression signature of IL35+ B cell subset in blood and surgically resected tissues from patients with PDAC. Additionally, we will evaluate anti-IL35 therapy in combination with immune checkpoint blockade as a novel therapeutic strategy in syngeneic murine PDAC models. Our proposed research will provide an understanding of a previously uncharacterized facet of B cell-mediated function in PDAC, use state-of-the-art PDAC murine models to test strategies that block immune suppressive pathways in TME to enhance the impact of T cell- reinvigorating therapies, and provide a quantitative and qualitative assessment of IL35+ B cells in human PDAC. This project will expand our understanding of how IL35 shapes the immunosuppressive tumor microenvironment and may inform the optimal design of B cell-directed immunotherapy strategies against pancreatic cancer.
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 immune suppression instigated by pancreatic tumor and stromal cells. We have identified IL35- producing B cells as important regulators of anti-tumor immune responses in pancreatic cancer, and our proposed research will shed light on the mechanisms by which these cells elicit pancreatic tumor growth and will provide us with novel therapeutic targets that could be used to synergize with existing immunotherapeutic approaches.