临床上抗雄性激素疗法或早或迟会导致前列腺癌去势抵抗。后者可能与肿瘤微环境密切相关，但其作用机制尚未阐明。免疫细胞亚群和特异分泌因子是微环境中的重要组成成分，可能在前列腺癌去势抵抗的形成中起着重要作用。我们前期已对前列腺癌去势抵抗及微环境的变化做了扎实的工作。预实验发现去势疗法导致PGE2及Gremlin1分泌增加；PGE2可诱导CD4low T细胞的生成，后者可通过释放IL4异常激活雄性激素受体（AR）； Gremlin1可诱导上皮间质转化并促进肿瘤干细胞形成。因此，本项目将研究“去势-释放PGE2-T细胞-IL4-异常激活AR”和“去势-释放Gremlin1-EMT-肿瘤干细胞”这两种可能途径及它们之间的联系，以期明确免疫细胞亚群和特异分泌因子等微环境因子是抗雄性激素疗法的新机制，确定关键的免疫细胞亚群和特异分泌因子作为靶点，为前列腺癌去势抵抗的临床诊治提供新的理论依据及新方法。

Clinically, androgen deprivation therapy will sooner or later leads to castration resistant prostate cancer (CRPC), which is believed to link to tumor microenvironment. However, the underlying mechanism is still unclear. Subpopulations of immune cells and specific secreted factors are important components of the tumor microenvironment and may play a crucial role during the development of CRPC. We have previously done solid work related to CRPC and changes of the tumor microenvironment after androgen deprivation. In our unpublished, preliminary study, we have found the following: 1) Following castration, secretion of PEG2 and Gremlin1 from the microenvironment increases; 2) PEG2 can induce and enrich production of CD4low T, which can in turn aberrantly activate AR via production of IL-4; 3) Gremlin1 can induce epithelial-mesenchymal transition (EMT) and development of tumor stem cells. Therefore, in this project, we will focus on “castration-secretion of PGE2-T cells-IL4-aberrent activation of AR” and “castration-secretion of Gremlin1-EMT-tumor stem cells” routes and the relationship between the two routes, to ascertain whether a subpopulation of immune cells and specific secreted factors in the tumor microenvironment play a crucial role during development of CRPC, whether they can be regarded as novel targets for the diagnosis and treatment of CRPC.