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

Tiziana Schioppa, Robert Moore, Richard G. Thompson, Elizabeth C. Rosser, Hagen Kulbe, Sergei Nedospasov, Claudia Mauri, Lisa M. Coussens, Frances R. Balkwill

Research output: Contribution to journalArticlepeer-review

274 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)10662-10667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Jun 28 2011
Externally publishedYes


  • Immune cells
  • Inflammation
  • Tumor microenvironment

ASJC Scopus subject areas

  • General


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