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

Abby Geis, Hongni Fan, Xinqun Wu, Shaoguang Wu, David L. Huso, Jaime L. Wolfe, Cynthia Louise Sears, Andrew Mark 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 1 2015

Fingerprint

Bacteroides fragilis
Regulatory T-Lymphocytes
Colon
Carcinogenesis
Inflammation
Neoplasms
Interleukin-2
Colitis
Inflammatory Bowel Diseases
Bacterial Infections
Colorectal Neoplasms
Homeostasis
Cytokines

ASJC Scopus subject areas

  • Oncology

Cite this

Regulatory T-cell response to enterotoxigenic bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis. / Geis, Abby; Fan, Hongni; Wu, Xinqun; Wu, Shaoguang; Huso, David L.; Wolfe, Jaime L.; Sears, Cynthia Louise; Pardoll, Andrew Mark; Housseau, Franck.

In: Cancer Discovery, Vol. 5, No. 10, 01.10.2015, p. 1098-1109.

Research output: Contribution to journalArticle

Geis, Abby ; Fan, Hongni ; Wu, Xinqun ; Wu, Shaoguang ; Huso, David L. ; Wolfe, Jaime L. ; Sears, Cynthia Louise ; Pardoll, Andrew Mark ; Housseau, Franck. / Regulatory T-cell response to enterotoxigenic bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis. In: Cancer Discovery. 2015 ; Vol. 5, No. 10. pp. 1098-1109.
@article{059f5b2c3ca648b4801891af238d3d4d,
title = "Regulatory T-cell response to enterotoxigenic bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis",
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.",
author = "Abby Geis and Hongni Fan and Xinqun Wu and Shaoguang Wu and Huso, {David L.} and Wolfe, {Jaime L.} and Sears, {Cynthia Louise} and Pardoll, {Andrew Mark} and Franck Housseau",
year = "2015",
month = "10",
day = "1",
doi = "10.1158/2159-8290.CD-15-0447",
language = "English (US)",
volume = "5",
pages = "1098--1109",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Regulatory T-cell response to enterotoxigenic bacteroides fragilis colonization triggers IL17-dependent colon carcinogenesis

AU - Geis, Abby

AU - Fan, Hongni

AU - Wu, Xinqun

AU - Wu, Shaoguang

AU - Huso, David L.

AU - Wolfe, Jaime L.

AU - Sears, Cynthia Louise

AU - Pardoll, Andrew Mark

AU - Housseau, Franck

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84943252054&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943252054&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-15-0447

DO - 10.1158/2159-8290.CD-15-0447

M3 - Article

C2 - 26201900

AN - SCOPUS:84943252054

VL - 5

SP - 1098

EP - 1109

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 10

ER -