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Cancer Res. 2016 Apr 15;76(8):2115-24. doi: 10.1158/0008-5472.CAN-15-0749. Epub 2016 Feb 15.

Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.

Author information

1
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. fhousse1@jhmi.edu.
2
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Flow Cytometry core, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Microbiology, University of Malaya, Kuala Lumpur, Malaysia.
7
Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia.
8
Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia. University of Malaya Cancer Research Institute, Kuala Lumpur, Malaysia.
9
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
10
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.

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.

PMID:
26880802
PMCID:
PMC4873376
DOI:
10.1158/0008-5472.CAN-15-0749
[Indexed for MEDLINE]
Free PMC Article

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