A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

被引:1298
作者
Wu, Shaoguang [1 ]
Rhee, Ki-Jong [1 ]
Albesiano, Emilia [2 ,3 ]
Rabizadeh, Shervin
Wu, Xinqun [1 ,2 ,3 ]
Yen, Hung-Rong [2 ,3 ,4 ,5 ]
Huso, David L. [6 ]
Brancati, Frederick L. [1 ]
Wick, Elizabeth [7 ]
McAllister, Florencia [1 ,2 ,3 ]
Housseau, Franck [2 ,3 ]
Pardoll, Drew M. [1 ,2 ,3 ]
Sears, Cynthia L. [1 ,2 ,3 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA
[4] Chang Gung Univ, Coll Med, Grad Inst Clin Med Sci, Tao Yuan, Taiwan
[5] Chang Gung Mem Hosp, Ctr Tradit Chinese Med, Tao Yuan, Taiwan
[6] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
ENTEROTOXIGENIC BACTEROIDES-FRAGILIS; COLITIS-ASSOCIATED CANCER; TUMOR MICROENVIRONMENT; COLORECTAL-CANCER; APC(MIN/+) MICE; MOUSE MODEL; INFLAMMATION; INFECTION; STAT3; IMMUNITY;
D O I
10.1038/nm.2015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (T(H)17) response distributed between CD4(+) T cell receptor-alpha beta (TCR alpha beta)(+) and CD4(-)8(-)TCR gamma alpha(+) T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying T(H)17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and T(H)17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.
引用
收藏
页码:1016 / U64
页数:8
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