Innate γδT Cells Are the Predominant IL-17-Producing Cells in Human Colorectal Cancer that Correlate Immunosuppression with Tumor-Elicited Inflammation

【作者】 黄建；

【机构】 浙江大学附属第二医院；

【摘要】 Background:Development of cancer has been linked to chronic inflammation,particularly IL-23/IL-17 pathway.However,the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer(CRC)remain poorly defined.Methods:We used multicolor flow cytometry analysis and primary cell separation technology to study the cellular source of IL-17 and inflammatory cells composition in human fresh tumor and paired normal tissues.To investigate the mechanism of γδT17 polarization in tumor,we used fluorescence-activated cell sorting and in vitro co-cuture experiment to study the impact of infDCs on γδT17 polarization and the role of γδT17 in tumor immunity.We also analysised the correlation between tumor infiltrating γδT17 and clinicopathological features of patients.Results:Here,we demonstrate that innate γδT cells are the major IL-17 producer( γδT17)in human CRC.Microbial products elicited by tumorous epithelial barrier disruption correlate with infDCs accumulation and γδT17 polarization in tumor.Activated infDCs induce γδT17 cells to secrete large amounts of IL-8,TNF-αand GM-CSF which appear to chemoattract PMN-MDSCs into the tumor and elicit immunosuppression.Importantly, γδT17 cell infiltration is positively correlated with TNM stages and other clinicopathological features.Conclusions:Our study uncovers a novel infDCs/ γδT17/PMN-MDSCs regulatory axis in human CRC with γδT17 at its core that correlates immunosuppression with tumor-elicited inflammation.These findings suggest that γδT17 cells may be key players in human CRC progression and have the potential for treatment or prognosis prediction.更多还原

【Abstract】 Background:Development of cancer has been linked to chronic inflammation,particularly IL-23/IL-17 pathway.However,the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer(CRC)remain poorly defined.Methods:We used multicolor flow cytometry analysis and primary cell separation technology to study the cellular source of IL-17 and inflammatory cells composition in human fresh tumor and paired normal tissues.To investigate the mechanism of γδT17 polarization in tumor,we used fluorescence-activated cell sorting and in vitro co-cuture experiment to study the impact of infDCs on γδT17 polarization and the role of γδT17 in tumor immunity.We also analysised the correlation between tumor infiltrating γδT17 and clinicopathological features of patients.Results:Here,we demonstrate that innate γδT cells are the major IL-17 producer( γδT17)in human CRC.Microbial products elicited by tumorous epithelial barrier disruption correlate with infDCs accumulation and γδT17 polarization in tumor.Activated infDCs induce γδT17 cells to secrete large amounts of IL-8,TNF-αand GM-CSF which appear to chemoattract PMN-MDSCs into the tumor and elicit immunosuppression.Importantly, γδT17 cell infiltration is positively correlated with TNM stages and other clinicopathological features.Conclusions:Our study uncovers a novel infDCs/ γδT17/PMN-MDSCs regulatory axis in human CRC with γδT17 at its core that correlates immunosuppression with tumor-elicited inflammation.These findings suggest that γδT17 cells may be key players in human CRC progression and have the potential for treatment or prognosis prediction.更多还原