AUTHOR=Michaud Daniel , Mirlekar Bhalchandra , Steward Colleen , Bishop Gail , Pylayeva-Gupta Yuliya 

TITLE=B Cell Receptor Signaling and Protein Kinase D2 Support Regulatory B Cell Function in Pancreatic Cancer

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.745873

DOI=10.3389/fimmu.2021.745873

ISSN=1664-3224

ABSTRACT=B cells can be potent suppressors of anti-tumor T cell immunity, presenting a mechanism of resistance to immunotherapy. In pancreatic ductal adenocarcinoma, B cells can display a T cell-suppressive phenotype centered on the expression of the cytokine IL-35. While, this immunosuppression presents a mechanism of resistance to immunotherapy, it is not clear how regulatory B cells could be targeted, and the signals that promote this suppressive phenotype in B cells are not well understood. Here we use a novel IL-35 reporter model to understand which signaling pathways are important for immunosuppressive properties in B cells. In vitro analysis of IL-35 reporter B cells revealed that synergy between the BCR and TLR4 signaling pathways is sufficient to induce IL-35 expression. However, in vivo, it is evident that the B cell receptor activation, as opposed to MyD88 signaling in B cells is central to B cell-mediated suppression and promotion of pancreatic cancer growth. Further analysis revealed protein kinase D2 (PKD2) as being one of the key downstream regulators of IL-35 expression in B cells. Regulatory B cells with an inactivating mutation in PKD2 failed to produce IL-35 and fully suppress effector T cell function in vitro. Furthermore, inhibition of PKD in B cells decreased tumor growth and suppressed effector T cell function upon adoptive transfer into B cell-deficient mice. Collectively, these data provide insight into how regulatory B cell function is promoted in pancreatic cancer and identify potential therapeutic targets to restrain this function.