B cell c-Maf signaling promotes tumor progression in animal models of pancreatic cancer and melanoma

Abstract

BackgroundThe role of B cells in anti-tumor immunity remains controversial, with studies suggesting the pro-tumor and anti-tumor activity. This controversy may be due to the heterogeneity in B cell populations, as the balance among the subtypes may impact tumor progression. The immunosuppressive regulatory B cells (Breg) release IL-10 but only represent a minor population. Additionally, tumor-specific antibodies (Ab) also exhibit anti-tumor and pro-tumor function dependent on the Ab isotype. Transcription factor c-Maf has been suggested to contribute to the regulation of IL-10 in Breg, but the role of B cell c-Maf signaling in anti-tumor immunity and regulating antibody responses remain unknown. MethodsConditional B cell c-Maf knockout (KO) and control mice were used to establish a KPC pancreatic cancer model and B16.F10 melanoma model. Tumor progression was evaluated. B cell and T cell phenotypes were determined by flow cytometry, mass cytometry, and cytokine/chemokine profiling. Differentially expressed genes in B cells were examined by using RNA-seq. Peripheral blood samples were collected from healthy donors and melanoma patients for B cell phenotyping. ResultsCompared to B cells from spleen and lymph nodes, B cells in the pancreas exhibited significantly less follicular phenotype and higher IL-10 production in naive mice. c-Maf deficiency resulted in a significant reduction of CD9+ IL-10-producing Breg in the pancreas. PDAC progression resulted in accumulation of circulating B cells with follicular phenotype and less IL-10 production in the pancreas. Notably, B cell c-Maf deficiency delayed PDAC tumor progression and resulted in pro-inflammatory B cells. Further, tumor volume reduction and increased effective T cells in the tumor-draining lymph node (TDLN) were observed in B cell c-Maf KO mice in the B16.F10 melanoma model. RNA-seq analysis of isolated B cells revealed that B cell c-Maf signaling modulates immunoglobulin (Ig)-associated genes and tumor specific antibody production. We furthermore demonstrated c-Maf-positive B cell subsets and increase of IL-10-producing B cells after incubation with IL-4 and CD40L in the peripheral blood of melanoma patients. ConclusionOur study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses. What is already known on this topicThe net effect of B cells on tumor immunity depends on the balance of various B cell subtypes. c-Maf has been suggested to contribute to the regulation of IL-10 in regulatory B cells (Breg), but the role of B cell c-Maf signaling in anti-tumor immunity remains unknown. What this study addsThis study shown that B cell c-Maf signaling drives tumor progression in pancreatic cancer and melanoma. We defined different anti-tumor mechanisms of B cell c-Maf deficiency in two tumor models. Specifically, c-Maf signaling modulates the pro-inflammatory phenotype of B cells in the KPC tumor-bearing pancreas and tumor-specific antibody responses in tumor draining lymph nodes (TDLN) of melanoma. How this study might affect research, practice or policyThese studies indicate that inhibition of c-Maf signaling is a novel and promising approach for immunotherapy in pancreatic cancer and melanoma.