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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Signaling

Background:

• B cells can suppress anti-tumor T cell immunity, contributing to immunotherapy resistance, particularly in pancreatic ductal adenocarcinoma.
• Regulatory B cells expressing Interleukin 35 (IL-35) are implicated in this immunosuppressive phenotype.
• The precise signaling pathways and molecular mechanisms driving regulatory B cell function in cancer remain incompletely understood.

Purpose of the Study:

• To elucidate the signaling pathways that promote immunosuppressive properties in B cells, specifically IL-35 expression.
• To identify key molecular regulators of B cell-mediated immunosuppression in pancreatic cancer.
• To explore potential therapeutic strategies targeting regulatory B cell function.

Main Methods:

• Utilized a novel IL-35 reporter model for B cells to investigate signaling pathways.
• Performed in vitro analysis of B cells stimulated via B cell receptor (BCR) and Toll-like receptor 4 (TLR4).
• Conducted in vivo studies assessing B cell receptor activation and MyD88 signaling.
• Identified and functionally characterized protein kinase D2 (PKD2) as a downstream regulator.
• Assessed the impact of PKD2 inhibition and adoptive transfer of modified B cells in mouse models.

Main Results:

• A synergy between BCR and TLR4 signaling was sufficient to induce IL-35 expression in vitro.
• In vivo, B cell receptor activation, not MyD88 signaling, was critical for B cell-mediated suppression and pancreatic tumor growth.
• Protein kinase D2 (PKD2) was identified as a key downstream regulator of IL-35 expression in B cells.
• Inactivating mutations in PKD2 abolished IL-35 production and T cell suppression by regulatory B cells.
• Inhibition of PKD in B cells reduced tumor growth and enhanced effector T cell function in vivo.

Conclusions:

• B cell receptor activation and downstream PKD2 signaling are central to the promotion of regulatory B cell function and IL-35 production in pancreatic cancer.
• Targeting PKD2 in B cells represents a promising therapeutic strategy to overcome immunosuppression and improve anti-tumor immunity.
• These findings provide critical insights into the mechanisms of B cell-mediated immune evasion in pancreatic cancer.