Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.
Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.
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DOI：
10.1158/0008-5472.can-15-0749
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发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Sears CL
中科院分区：
文献类型：
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作者：
Housseau F;Wu S;Wick EC;Fan H;Wu X;Llosa NJ;Smith KN;Tam A;Ganguly S;Wanyiri JW;Iyadorai T;Malik AA;Roslani AC;Vadivelu JS;Van Meerbeke S;Huso DL;Pardoll DM;Sears CL
产生il -17的Th17细胞，通过stat3依赖机制产生，已被证明在许多系统中促进致癌，包括微生物驱动的结肠癌。IL-17的其他来源，如γδ T细胞，在炎症条件下可用，但它们对癌症发展的贡献尚不清楚。在这项研究中，我们用人类肠道细菌，产肠毒素的脆弱拟杆菌（ETBF）定植MinApc+/-小鼠，模拟th17驱动的结肠肿瘤发生，以研究炎症和结直肠癌之间的联系。我们发现，通过敲除CD4+ T细胞中的Stat3来切除Th17细胞可以延缓肿瘤的发生，但不能抑制结肠肿瘤的最终形成。然而，IL-17阻断显著减弱了肿瘤的形成，这表明IL-17在肿瘤发生中是一个关键的需要，但来自Th17细胞以外的来源。值得注意的是，在etbf定植的th17缺陷Min小鼠中，γδ T细胞的基因消融阻止了结肠肿瘤的晚期出现。综上所述，这些发现支持适应性Th17细胞和先天γδT17细胞衍生的IL-17在细菌诱导的结肠癌发生中的冗余作用，强调了治疗靶向细胞因子本身而不是其细胞来源的重要性。
IL-17-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 IL-17, 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 MinApc+/- 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, IL-17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL-17 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 IL-17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources.