Elimination of CD4^low HLA-G^＋ T cells overcomes castration- resistance in prostate cancer therapy  

作　　者：Chao Wang Jiahuan Chen Qianfei Zhang Wang Li Shengbo Zhang Yanjie Xu Fang Wang Bing Zhang Yan Zhang Wei-Qiang Gao Chao Wang;Jiahuan Chen;Qianfei Zhang;Wang Li;Shengbo Zhang;Yanjie Xu;Fang Wang;Bing Zhang;Yan Zhang;Wei-Qiang Gao(State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University,Shanghai 200030, China;Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China;Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biamedicine, Shanghai Jiao Tong University, Shanghai 200240, China)

机构地区：[1]State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University,Shanghai 200030, China [2]Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China [3]Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biamedicine, Shanghai Jiao Tong University, Shanghai 200240, China

出　　处：《Cell Research》2018年第11期1103-1117,共15页细胞研究（英文版）

摘　　要：Androgen deprivation therapy （ADT） is a main treatment for prostate cancer （PCa） but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer （CRPC）. In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here we identified a novel population of CD4~~WHLA-G^＋ T cells that undergo significant expansion in PCa patients after ADT. in mouse PCa models, a similar CD4^low T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH1 7 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4^low HLA-G^＋ T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11 b^low F4/80^hi macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4^low naTve T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4^low HLA-G^＋ T cells appeared, but not immediately following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4^low HLA- G^＋ T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition for the treatment of prostate cancer.

关 键 词：HLA-G CD4 治疗学 前列腺 房间 癌症 阉割 CELECOXIB 

分 类 号：Q343[生物学—遗传学] X51[环境科学与工程—环境工程]