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

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 observedwhen B cells from Tnf ^-/- mice were transferred to Rag2 ^-/- mice or when TNF-α was eliminated selectively in B cells. Resistance to papilloma developmentin 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.