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: Tiziana Schioppa, Robert Moore, Richard G Thompson, Elizabeth C Rosser, Hagen Kulbe, Sergei Nedospasov, Claudia Mauri, Lisa M Coussens, Frances R Balkwill
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 26 Pg. 10662-7 (Jun 28 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21670304 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• Tumor Necrosis Factor-alpha
• 9,10-Dimethyl-1,2-benzanthracene

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Adoptive Transfer
• Animals
• B-Lymphocytes (immunology)
• Carcinogens (toxicity)
• Carcinoma, Squamous Cell (chemically induced, immunology, pathology)
• Immunohistochemistry
• Mice
• Mice, Knockout
• Skin Neoplasms (chemically induced, immunology, pathology)
• Tumor Necrosis Factor-alpha (genetics, physiology)