BTK SIGNALING DRIVES CD1d(hi)CD5(+) REGULATORY B CELL DIFFERENTIATION TO PROMOTE PANCREATIC CARCINOGENESIS

The immune microenvironment of pancreatic ductal adenocarcinoma (PDAC) is comprised of a heterogeneous population of cells that are critical for disease evolution. Prominent among these are the specialized CD1d(hi)CD5(+) regulatory B (B(reg)) cells that exert a pro-tumorigenic role by promoting tumor cell proliferation. Dissecting the molecular pathways regulating this immune sub-population can thus be valuable for uncovering potential therapeutic targets. Here, we investigate Bruton’s Tyrosine Kinase (BTK), a key B cell kinase, as a potential regulator of CD1d(hi)CD5(+) B(reg) differentiation in the pancreatic tumor microenvironment. Treatment of cytokine-induced B cells in vitro with the high specificity BTK inhibitor Tirabrutinib inhibited CD1d(hi)CD5(+) B(reg) differentiation and production of IL-10 and IL-35, essential mediators of B(reg) immunosuppressive functions. The BTK signaling pathway was also found to be active in vivo in PanIN-associated regulatory B cells. Tirabrutinib treatment of mice bearing orthotopic Kras(G12D)-pancreatic lesions severely compromised stromal accumulation of the CD1d(hi)CD5(+) B(reg) population. This was accompanied by an increase in stromal CD8(+)IFNγ(+) cytotoxic T cells and significant attenuation of tumor cell proliferation and PanIN growth. Our results uncover a novel role for BTK in regulating CD1d(hi)CD5(+) B(reg) differentiation and emphasize its potential as a therapeutic target for pancreatic cancer.