title: B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis.
abstract: 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.
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Schioppa
authors.forename: Robert
authors.initials: R
authors.lastname: Moore
authors.forename: Richard G
authors.initials: RG
authors.lastname: Thompson
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Rosser
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Sergei
authors.initials: S
authors.lastname: Nedospasov
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D002273:Carcinogens; D014409:Tumor Necrosis Factor-alpha; D015127:9,10-Dimethyl-1,2-benzanthracene