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. In vitro 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, in vivo, 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 in vitro. 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with few viable treatment options for late-stage tumors resulting in a 10% 5-year survival rate [1]
This study addresses the respective roles of B cell receptor (BCR) and TLR4 signaling by B cells in pancreatic cancer and how they regulate expression of Interleukin 35 (IL-35)
We recently showed that decrease in IL-35 production by B cells in PDAC results in significantly increased effector T cell responses coupled with decreased tumor growth [6]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with few viable treatment options for late-stage tumors resulting in a 10% 5-year survival rate [1]. We previously identified B cells as key suppressors of T cell infiltration and effector function within pancreatic tumors, predominantly through production of the cytokine IL-35 [5, 6]. The key regulators of this suppressive activity by B cells in the tumor microenvironment are still unclear. Immunosuppressive or ‘regulatory’ B cells were originally identified in many disease contexts outside of cancer. The contribution of these B cell populations on disease regulation has been primarily linked to expression of anti-inflammatory IL10 by to suppress host T cell responses [7,8,9,10]. To enable studies on regulation of IL-35 expression in B cells, we generated an Il12a-GFP reporter mouse [18] to accompany a previously generated Ebi3-TdTomato reporter mouse [19]
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