UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.
The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville, Louisville, Kentucky, USA.
J Immunother Cancer. 2024 Nov 27;12(11):e009861. doi: 10.1136/jitc-2024-009861.
The 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.
Conditional 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.
Compared 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.
Our study highlights that B cell c-Maf signaling drives tumor progression through the modulation of Breg, inflammatory responses, and tumor-specific Ab responses.
B 细胞在抗肿瘤免疫中的作用仍存在争议，有研究表明其具有促肿瘤和抗肿瘤活性。这种争议可能是由于 B 细胞群体的异质性所致，因为亚群之间的平衡可能会影响肿瘤的进展。具有免疫抑制功能的调节性 B 细胞（Breg）会释放白细胞介素 10（IL-10），但仅占很小的一部分。此外，肿瘤特异性抗体（Abs）也表现出依赖于 Ab 同种型的抗肿瘤和促肿瘤功能。转录因子 c-Maf 被认为有助于 Breg 中 IL-10 的调节，但 B 细胞 c-Maf 信号在抗肿瘤免疫和调节 Ab 反应中的作用仍不清楚。
使用条件性 B 细胞 c-Maf 敲除（KO）和对照小鼠建立 KPC 胰腺导管腺癌模型和 B16.F10 黑色素瘤模型。评估肿瘤进展情况。通过流式细胞术、质谱流式细胞术和细胞因子/趋化因子谱分析确定 B 细胞和 T 细胞表型。通过 RNA 测序（RNA-seq）检测 B 细胞中差异表达的基因。收集健康供者和黑色素瘤患者的外周血样本进行 B 细胞表型分析。
与脾脏和淋巴结（LN）中的 B 细胞相比，未成熟小鼠胰腺中的 B 细胞滤泡表型显著减少，IL-10 产生增加。c-Maf 缺失导致胰腺中 CD9+IL-10 产生的 Breg 显著减少。胰腺导管腺癌（PDAC）进展导致循环 B 细胞的积累，其具有滤泡表型，胰腺中 IL-10 的产生减少。值得注意的是，B 细胞 c-Maf 缺失可延缓 PDAC 肿瘤的进展，并导致促炎 B 细胞。此外，在 B16.F10 黑色素瘤模型中，c-Maf KO 小鼠的肿瘤体积减小，肿瘤引流淋巴结中的有效 T 细胞增加。对分离的 B 细胞进行 RNA-seq 分析表明，B 细胞 c-Maf 信号通过调节 Breg、炎症反应和肿瘤特异性 Ab 产生来调节免疫球蛋白相关基因。我们还在黑色素瘤患者的外周血中发现了 c-Maf 阳性 B 细胞亚群和在 IL-4 和 CD40L 孵育后 IL-10 产生增加的 B 细胞。
本研究强调了 B 细胞 c-Maf 信号通过调节 Breg、炎症反应和肿瘤特异性 Ab 反应来驱动肿瘤的进展。
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