TY - JOUR
T1 - Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis
AU - Housseau, Franck
AU - Wu, Shaoguang
AU - Wick, Elizabeth C.
AU - Fan, Hongni
AU - Wu, Xinqun
AU - Llosa, Nicolas J.
AU - Smith, Kellie N.
AU - Tam, Ada
AU - Ganguly, Sudipto
AU - Wanyiri, Jane W.
AU - Iyadorai, Thevambiga
AU - Malik, Ausama A.
AU - Roslani, April C.
AU - Vadivelu, Jamunarani S.
AU - Van Meerbeke, Sara
AU - Huso, David L.
AU - Pardoll, Drew M.
AU - Sears, Cynthia L.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - 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 Apc+/-ice 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 gd 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 gdT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources.
AB - 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 Apc+/-ice 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 gd 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 gdT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources.
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U2 - 10.1158/0008-5472.CAN-15-0749
DO - 10.1158/0008-5472.CAN-15-0749
M3 - Article
C2 - 26880802
AN - SCOPUS:84965167363
SN - 0008-5472
VL - 76
SP - 2115
EP - 2124
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -