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

Daniel Michaud; Bhalchandra Mirlekar; Colleen Steward; Gail Bishop; Yuliya Pylayeva-Gupta

doi:10.3389/fimmu.2021.745873

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

Journal article

Open access

Peer reviewed

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

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

Frontiers in immunology, Vol.12, pp.745873-745873

2021

DOI: 10.3389/fimmu.2021.745873

PMCID: PMC8761795

PMID: 35046933

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https://doi.org/10.3389/fimmu.2021.745873View

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Abstract

B cells can act as 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 or regulatory phenotype centered on the expression of the cytokine Interleukin 35 (IL-35). While B cell-mediated immunosuppression presents a barrier to anti-tumorigenic T cell function, it is not clear how regulatory B cell function 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. analysis of IL-35 reporter B cells revealed a synergy between the BCR and TLR4 signaling pathways is sufficient to induce IL-35 expression. However, , 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 identified protein kinase D2 (PKD2) as being a key downstream regulator of IL-35 expression in B cells. Regulatory B cells with an inactivating mutation in PKD2 failed to produce IL-35 or fully suppress effector T cell function . Furthermore, inhibition of PKD in B cells decreased tumor growth and promoted 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.

Animals

B-Lymphocytes, Regulatory - immunology

Carcinoma, Pancreatic Ductal - immunology

Interleukins - biosynthesis

Interleukins - immunology

Mice

Mice, Inbred C57BL

Pancreatic Neoplasms - immunology

Protein Kinase D2 - immunology

Receptors, Antigen, B-Cell - immunology

Signal Transduction - immunology

Details

Title: Subtitle: B Cell Receptor Signaling and Protein Kinase D2 Support Regulatory B Cell Function in Pancreatic Cancer
Creators: Daniel Michaud - University of North Carolina at Chapel Hill
Bhalchandra Mirlekar - University of North Carolina at Chapel Hill
Colleen Steward - University of North Carolina at Chapel Hill
Gail Bishop - University of Iowa
Yuliya Pylayeva-Gupta - University of North Carolina at Chapel Hill
Resource Type: Journal article
Publication Details: Frontiers in immunology, Vol.12, pp.745873-745873
DOI: 10.3389/fimmu.2021.745873
PMID: 35046933
PMCID: PMC8761795
NLM abbreviation: Front Immunol
ISSN: 1664-3224
eISSN: 1664-3224
Grant note: R37 CA230786 / NCI NIH HHS T32 CA071341 / NCI NIH HHS F31 CA239494 / NCI NIH HHS P30 CA016086 / NCI NIH HHS
Language: English
Date published: 2021
Academic Unit: Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984297437002771

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