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

• Published in: Journal for immunotherapy of cancer 2024-11, Vol.12 (11), p.e009861
• Main Authors: Zhong, Qian, Hao, Hongying, Li, Shu, Ning, Yongling, Li, Hong, Hu, Xiaoling, McMasters, Kelly M, Yan, Jun, Ding, Chuanlin
• Format: Article
• Language: English
• Subjects: Animals; B cell; B-Lymphocytes, Regulatory - immunology; B-Lymphocytes, Regulatory - metabolism; Basic Tumor Immunology; Cell growth; Cell Line, Tumor; Cytokines; Disease Models, Animal; Disease Progression; Female; Flow cytometry; Genotype & phenotype; Humans; Immune modulatory; Immunoglobulins; Interleukin-10 - metabolism; Leukocytes; Lymphatic system; Lymphocytes; Melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Original Research; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins c-maf - metabolism; Signal Transduction; Spleen; Transcription factors; Tumor microenvironment - TME
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2024-009861

BackgroundThe role of B cells in antitumor immunity remains controversial, with studies suggesting the protumor and antitumor 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 interleukin 10 (IL-10) but only represent a minor population. Additionally, tumor-specific antibodies (Abs) also exhibit antitumor and protumor functions 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 antitumor immunity and regulating Ab responses remains 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 sequencing (RNA-seq). Peripheral blood samples were collected from healthy donors and patients with melanoma for B cell phenotyping.ResultsCompared with B cells from the spleen and lymph nodes (LN), B cells in the pancreas exhibited significantly less follicular phenotype and higher IL-10 production in naïve mice. c-Maf deficiency resulted in a significant reduction of CD9+ IL-10-producing Breg in the pancreas. Pancreatic ductal adenocarcinoma (PDAC) progression resulted in the accumulation of circulating B cells with the follicular phenotype and less IL-10 production in the pancreas. Notably, B cell c-Maf deficiency delayed PDAC tumor progression and resulted in proinflammatory B cells. Further, tumor volume reduction and increased effective T cells in the tumor-draining LN 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-associated genes and tumor-specific Ab production. We furthermore demonstrated c-Maf-positive B cell subsets and an increase of IL-10-producing B cells after incubation with IL-4 and CD40L in the peripheral blood of patients with melanoma.ConclusionOur study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses.