Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10662-7. doi: 10.1073/pnas.1100994108. Epub 2011 Jun 13.
The inflammatory cytokine TNF-α has been recognized as a critical tumor promoter, but the effector cells that mediate its action have not been fully characterized. Because B cells regulate squamous and prostate carcinogenesis, and Tnf(-/-) mice harbor B-cell defects, we investigated the hypothesis that B cells are important effector cells for TNF-α-mediated promotion of cancer development. Using an adoptive transfer strategy and the 7,12-dimethylbenz[α]anthracene/terephthalic acid (DMBA/TPA) two-stage model of skin carcinogenesis, we found that both B cells and TNF-α are critical for the development of DMBA/TPA-induced papilloma. Transfer of B cells from DMBA/TPA-treated wild-type mice to Tnf(-/-) mice rescued papilloma development to a wild-type level, a result not observed when B cells from Tnf(-/-) mice were transferred to Rag2(-/-) mice or when TNF-α was eliminated selectively in B cells. Resistance to papilloma development in Tnf(-/-) mice was associated with increased IFN-γ and CD8(+) T cells in skin and a significant reduction in IL-10-producing B regulatory cells alongside an increase in IFN-γ-producing CD8(+) T cells in the spleen. These data indicate that during DMBA/TPA-induced squamous carcinogenesis TNF-α mediates tumor-promoting activity via regulatory B cells that repress antitumor immunity.
炎症细胞因子 TNF-α 已被认为是一种关键的肿瘤促进剂，但介导其作用的效应细胞尚未得到充分表征。由于 B 细胞调节鳞状细胞癌和前列腺癌的发生，并且 Tnf(-/-) 小鼠存在 B 细胞缺陷，我们假设 B 细胞是 TNF-α 介导的促进癌症发展的重要效应细胞。我们使用过继转移策略和 7,12-二甲基苯并[a]蒽/对苯二甲酸（DMBA/TPA）皮肤致癌作用的两阶段模型，发现 B 细胞和 TNF-α 对于 DMBA/TPA 诱导的乳头状瘤的发展都是至关重要的。从 DMBA/TPA 处理的野生型小鼠向 Tnf(-/-) 小鼠转移 B 细胞可挽救乳头状瘤的发展，使其达到野生型水平，而从 Tnf(-/-) 小鼠转移 B 细胞至 Rag2(-/-) 小鼠或选择性消除 B 细胞中的 TNF-α 则不会观察到这种结果。Tnf(-/-) 小鼠对乳头状瘤发展的抗性与皮肤中 IFN-γ 和 CD8(+) T 细胞的增加以及 B 调节细胞中 IL-10 产生的减少以及脾脏中 IFN-γ 产生的 CD8(+) T 细胞的增加有关。这些数据表明，在 DMBA/TPA 诱导的鳞状细胞癌发生过程中，TNF-α 通过抑制抗肿瘤免疫的调节 B 细胞介导肿瘤促进活性。
