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The immune microenvironment of pancreatic ductal adenocarcinoma (PDA) 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.

BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis