title: Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.
abstract: IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. fhousse1@jhmi.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wick
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hongni
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Llosa
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kellie N
authors.initials: KN
authors.lastname: Smith
authors.affiliation: Flow Cytometry core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ada
authors.initials: A
authors.lastname: Tam
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jane W
authors.initials: JW
authors.lastname: Wanyiri
authors.affiliation: Department of Microbiology, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Thevambiga
authors.initials: T
authors.lastname: Iyadorai
authors.affiliation: Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ausama A
authors.initials: AA
authors.lastname: Malik
authors.affiliation: Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia. University of Malaya Cancer Research Institute, Kuala Lumpur, Malaysia.
authors.forename: April C
authors.initials: AC
authors.lastname: Roslani
authors.affiliation: Department of Microbiology, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Jamunarani S
authors.initials: JS
authors.lastname: Vadivelu
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Meerbeke
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D063646:Carcinogenesis; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D015704:CD4 Antigens; D020381:Interleukin-17