B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis

The inflammatory cytokine TNF-alpha 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-alpha-mediated promotion of cancer development. Using an adoptive transfer strategy and the 7,12-dimethylbenz[a] anthracene/terephthalic acid (DMBA/TPA) two-stage model of skin carcinogenesis, we found that both B cells and TNF-alpha 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 observedwhen B cells from Tnf(-/-) mice were transferred to Rag2(-/-) mice or when TNF-alpha was eliminated selectively in B cells. Resistance to papilloma developmentin Tnf(-/-) mice was associated with increased IFN-gamma and CD8(+) T cells in skin and a significant reduction in IL-10-producing B regulatory cells alongside an increase in IFN-gamma-producing CD8(+) T cells in the spleen. These data indicate that during DMBA/TPA-induced squamous carcinogenesis TNF-alpha mediates tumor-promoting activity via regulatory B cells that repress antitumor immunity.