文献类型：期刊文献

英文题名：Tumor-derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression

作者：Luo, Chubin[1,2];Xin, Haoyang[1,2];Zhou, Zhengjun[1,2];Hu, Zhiqiang[1,2];Sun, Rongqi[1,2];Yao, Na[1,2];Sun, Qiman[1,2];Borjigin, Uyunbilig[3];Wu, Xia[4];Fan, Jia[1,2,5];Huang, Xiaowu[1,2];Zhou, Shaolai[1,2];Zhou, Jian[1,2,5]

机构：[1]Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Dept Liver Surg & Transplantat, 136 Yi Xue Yuan Rd, Shanghai 200032, Peoples R China;[2]Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Shanghai, Peoples R China;[3]Inner Mongolia Univ, Coll Life Sci, State Key Lab Reprod Regulat & Breeding Grassland, Hohhot, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[5]Fudan Univ, State Key Lab Genet Engn, Shanghai, Peoples R China

年份：2022

卷号：76

期号：4

起止页码：982

外文期刊名：HEPATOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000762091200001)】；

基金：The National Key R&D Program of China (2019YFC1315800, 2019YFC1315802, and 2018YFA0109400); Major Special Projects of the Ministry of Science and Technology (2018ZX10302207); the National Natural Science Foundation of China (81830102, 81772578, 81972708, 81773069, 91942313, and 82173260); the Shanghai Rising-Star Program (18QA1401200); the Shanghai Technical Standard Program (21DZ2201100); the Original Scientific Personalized Support Project of Fudan University (IDF152064/015); and the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2018YQ14)

语种：英文

摘要：Background and Aims Macrophages are prominent components of solid tumors and exhibit distinct functions in different tumor microenvironments. Exosomes are emerging as necessary mediators of the cross-talk between tumor cells and the microenvironment. However, the underlying mechanisms of exosomes involving into crosstalk between tumor cells and macrophages during disease progression of intrahepatic cholangiocarcinoma (ICC) have not been yet fully realized. Approach and Results We found that the macrophages of ICC tumor tissues up-regulated the expression levels of immunosuppressive molecule programmed death-ligand 1 (PD-L1). Increased PD-L1(+) macrophages in tumor tissues effectively suppressed T-cell immunity and correlated with poor survival rates in patients with ICC. High-throughput RNA-sequencing analysis that was performed to identify differential levels of microRNAs (miRNAs) between exosomes derived from ICC cells and primary human intrahepatic biliary epithelial cells revealed that miR-183-5p was increased in ICC cell-derived exosomes. Exosomal miR-183-5p inhibited phosphatase and tensin homolog (PTEN) expression, to subsequently affect the elevations on both phosphorylated AKT and PD-L1 expression in macrophages. Furthermore, macrophages that treated with ICC cell-derived exosomes significantly suppressed T-cell immunity in vitro and contributed to the growth and progression of ICC in vivo, which were reversible through blockages on PD-L1 of these macrophages. Finally, clinical data showed that up-regulated levels of plasma exosomal miR-183-5p correlated with poor prognosis of patients with ICC after curative resection. Conclusions Tumor-derived exosomal miR-183-5p up-regulates PD-L1-expressing macrophages to foster immune suppression and disease progression in ICC through the miR-183-5p/PTEN/AKT/PD-L1 pathway. Exosomal miR-183-5p is a potential predictive biomarker for ICC progression and a potential target for development of therapeutic strategies against immune tolerance feature of ICC.