Yuliya Pylayeva-Gupta, PhD (Assistant Professor) is the PI on a new award from the V Foundation for Cancer Research.
The project titled “Mechanisms of pancreatic cancer-driven re-programming of tumor promoting B lymphocytes” is focused on elucidating molecular mechanisms by which pancreatic cancer promotes formation of and induces cytokine production in regulatory B cells. Yuliya’s laboratory has demonstrated that B cells expressing the immunomodulatory cytokine IL35 are necessary to support the growth of PDAC in murine models and that IL35 suppresses anti-tumor immune responses and promotes resistance to immunotherapy in PDAC. In Aim 1, they will clarify how B cell receptor (BCR) and endosomal Toll-like Receptor (TLR) signaling contribute to induction of IL35 expression in tumor-reactive B cells. To accomplish this task, they will analyze mouse models expressing a fixed BCR with or without antigen exposure, as well as mouse models lacking TLR signaling in B cells. The lab will also perform signaling pathway analysis in primary B cells and B cell lines. In Aim 2, they will define the role for IL35 in promoting regulatory cell development and function in PDAC using B cell specific knockout of IL35 and ex vivo signaling analyses in B cells. The proposed research will provide an understanding of a previously uncharacterized facet of B cell-mediated function in PDAC by using state-of-the-art PDAC murine models to test strategies that block immune suppressive pathways in the tumor microenvironment. 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.