激素非依赖性前列腺癌（CRPC）的形成是大多数前列腺癌治疗的最终结果，也是患者主要致死因素，但其形成的具体机制仍不明确。以往研究主要从肿瘤自身找原因，而忽略肿瘤微环境，特别是免疫细胞，对CRPC的调控作用。我们在自发前列腺癌TRAMP小鼠中成功建立CRPC模型，证实CD8+ T细胞是肿瘤基质中主要的免疫细胞，且首次发现CRPC中CD8+ T细胞共刺激分子CD28表达显著降低，主要为CD8+CD28- T细胞。体外实验发现CD8+CD28- T细胞与前列腺癌细胞共培养，可诱导其发生雄激素非依赖性生长及上皮间质转化。本课题拟继续在PTEN敲除小鼠自发前列腺癌模型和临床标本中验证CD8+CD28- T细胞与CRPC的相关性，探讨其诱导CRPC形成的分子机制，寻找介导其作用的细胞因子。本项目将揭示CRPC形成中的免疫调节新机制，并为CRPC早期无创诊断提供可行性指标，为CRPC的治疗提供新的靶标。

Castration-resistant Prostate Cancer (CRPC) is the final stage during most of prostate cancer treatment and is also the major reason for patient death. However, the mechanism of CRPC is still not clear. Most of previous research focused on tumor cells and ignored the effect of tumor microenvironment, especially the immune cells in the stroma, on CRPC formation. In our preliminary data, we successfully established the CRPC model in TRAMP mice which can develop the spontaneous prostate cancer, and proved that CD8+ T cells are the major immune cells in the tumor microenvironment. What's important, we first found that the coactivating molecular CD28 is low-expression and the major type of CD8+ T cells is CD8+CD28- T cells in tumor microenviroment of CRPC compared to non-castrated TRAMP mice. In vitro experiment showed that co-culture of CD8+CD28- T cells and prostate cancer cells induced epithelial-mesenchymal transition and androgen-independent growth of cancer cells. This project plans to confirm the correlation between CD8+CD28- T cells and CRPC in another spontaneous prostate cancer model - Pten KO mice and clinic prostate cancer patients; explore the mechanism on CD8+CD28- T cells inducing CRPC; find out which molecular mediates the function of CD8+CD28- T cells. This project will found the new immune regulation of CRPC formation, and provide the feasible indicator for early diagnosis of CRPC and new target for treatment of CRPC.