B7-H4/AR正反馈调节及介导的免疫逃避在前列腺癌去势抵抗中的机制研究

The functional status of androgen receptor (AR) and immune evasion are important factors in the development and castration resistance of prostate cancer, and aberrant activation of AR is closely related to immune microenvironment of prostate cancer. Some literatures reported that Immune checkpoint B7-H4 expresses abnormally in prostate cancer and induces T cell anergy, and B7-H4 is regulated by JAK/STAT signaling. The immunocyte phenotype of prostate cancer was preliminarily identified and the applicant found that B7-H4 was not only regulated by androgen/AR, but also could trans-activate AR through JAK2/STAT3 signaling pathway. Based on the above description, we speculate that B7-H4 may play an important role in the development of prostate cancer from hormone-dependent to castration-resistant, and a positive feedback network is constituted by B7-H4, AR and JAK2/STAT3 which promote the proliferation, immune evasion and castration resistance of prostate cancer. With the objective of verifying the scientific hypothesis, we will further identify the immune microenvironment in prostate cancer and explore the relationship among B7-H4, AR and JAK2/STAT3 signaling pathway at the cell, tissue and animal levels by flow cytometry, immunohistochemistry, transplanted tumor model in vitro and in vivo. This project may help to provide new strategies and ideas for anti-androgen therapy and immunotherapy of prostate cancer.

雄激素受体(AR)功能状态和免疫逃避是前列腺癌(PCa)发生发展及去势抵抗的重要因素，AR异常激活与PCa免疫微环境密切相关。文献报道免疫检查点B7-H4在PCa中异常表达并诱导T细胞失能，B7-H4受JAK/STAT信号通路调控；申请者前期初步鉴定了PCa的免疫细胞表型，并发现B7-H4不仅受雄激素/AR调控，而且依赖JAK2/STAT3途径反式调节AR的表达。据此，我们推测B7-H4可能在PCa发生发展及由激素依赖向去势抵抗的转化中起关键作用，其中B7-H4与AR和JAK2/STAT3形成正反馈放大信号通路，促进了PCa的增殖、免疫逃避和去势抵抗。为验证这一科学假说，本项目拟从细胞、组织和动物水平，通过流式细胞术、免疫组化、荷瘤模型等技术分别探讨PCa的免疫微环境及B7-H4与AR和JAK2/STAT3信号通路的相关性，为PCa抗雄治疗联合免疫治疗提供新的策略和思路。

B7-H4属于B7免疫球蛋白超家族，是一类免疫共刺激分子，其所介导的B7-CD28信号通路在肿瘤细胞发生免疫逃逸发挥关键作用。免疫逃逸和雄激素受体（AR）是前列腺癌（PCa）发生发展及去势抵抗的重要因素，而B7-H4在前列腺癌的去势抵抗进展及其免疫逃逸发挥的作用及其机制尚不清楚。课题组前期研究发现B7-H4随前列腺癌进展而表达增加，雄激素刺激下B7-H4表达增加，敲低B7-H4后AR表达相应减少，据此推测B7H4/AR正反馈调节及介导的免疫逃逸促使PCa发生去势抵抗进展。.基于上述科学假说，本实验从临床水平、细胞水平、动物水平三个层面研究B7-H4与AR的相互作用及其在PCa去势抵抗的作用。得出以下结果：（1）PCa患者全身循环及肿瘤组织局部均处于免疫抑制状态，且免疫抑制状态与前列腺癌进展呈正相关；（2）B7-H4参与了PCa去势抵抗进展；（3）AR作为B7-H4的转录因子转录合成B7-H4，B7-H4的表达增加正反馈促使AR表达；（4）B7-H4表达水平的降低可抑制体内PCa生长。.本实验结果显示B7-H4与AR正反馈相互促进表达，促使PCa去势抵抗进展，揭示了PCa发生去势抵抗的新机制，为抑制PCa发生去势抵抗进展提供新的策略和思路；另外本实验显示免疫抑制状态与PCa进展正相关，B7-H4可影响前列腺癌肿瘤组织的生长，为PCa的治疗方案和改善PCa患者临床预后及生存提供新的思路。