Regulatory T-cell response to enterotoxigenic bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis

Abby L. Geis, Hongni Fan, Xinqun Wu, Shaoguang Wu, David L. Huso, Jaime L. Wolfe, Cynthia L. Sears, Drew M. Pardoll, Franck Housseau

Research output: Contribution to journalArticle

Abstract

Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis. SIGNIFICANCE: Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production.

Original languageEnglish (US)
Pages (from-to)1098-1109
Number of pages12
JournalCancer discovery
Volume5
Issue number10
DOIs
StatePublished - Oct 2015

ASJC Scopus subject areas

  • Oncology

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