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

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.

Identification of MBOAT2 as an Unfavorable Biomarker Correlated with KRAS Activation and Reduced CD8+ T-Cell Infiltration in Pancreatic Cancer

“…Similarly, we found an obviously positive correlation between cytolytic activity, the infiltration level of DCs, and T-cell costimulation (Figure S1 ). It has been reported that B-cell receptor signaling played an important role in PC and that B-cells could influence the exclusion of CD8 + T-cells through IL35 [ 31 – 33 ]. But there is no obvious correlation between MBOAT2 level and B-cells from the ssGSEA analysis of the TCGA, GSE62452, GSE79668, and GSE60979 cohort (Figure S2 ).…”

Bioinformatics-Based Approach for Exploring the Immune Cell Infiltration Patterns in Alzheimer’s Disease and Determining the Intervention Mechanism of Liuwei Dihuang Pill

“… 45 , 68 Further studies have found that B cell receptors play an essential role in maintaining the survival, proliferation, and differentiation of B cells. 69 , 70 Therefore, inhibiting the activation of the B cell receptor-signaling pathway is of great significance in improving AD neuroinflammation and immune damage. 71 , 72 In the brain, HIV-1 can not only cause neuroinflammation and neuronal death by infecting immune cells (such as macrophages) but also lead to the abnormal elevation of Aβ, thereby affecting cognitive function.…”

Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions

“…55 However, another study showed that inhibition of PKD could abrogate immunosuppressive properties of B cells and thereby promote effector T-cell function. 74 In the later study, CRT0066101 suppressed the growth of orthotopic pancreatic xenograft tumors in immunocompetent mice, demonstrating its viability as an anticancer agent despite its potential complications in the immune system. Overall, these studies have established CRT0066101 as an orally effective anticancer agent in multiple solid tumor models.…”

“…It is interesting to note that a recent study demonstrated a concerning effect of CRT0066101 in antagonizing the anti-PD-1 immunotherapy by blocking AKT reactivation in T cells . However, another study showed that inhibition of PKD could abrogate immunosuppressive properties of B cells and thereby promote effector T-cell function . In the later study, CRT0066101 suppressed the growth of orthotopic pancreatic xenograft tumors in immunocompetent mice, demonstrating its viability as an anticancer agent despite its potential complications in the immune system.…”