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.
Cell Res. 2018 Nov;28(11):1103-1117. doi: 10.1038/s41422-018-0089-4. Epub 2018 Oct 8.
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 CD4HLA-G T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4 T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing T17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4HLA-G T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11bF4/80 macrophages. Furthermore, following androgen deprivation, elevated PGE-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4 naïve T cells towards the IL-4-expressing T17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE signaling with celecoxib at a time when CD4HLA-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 CD4HLA-G T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE inhibition for the treatment of prostate cancer.
雄激素剥夺疗法（ADT）是前列腺癌（PCa）的主要治疗方法，但几乎所有患者的疾病都会复发并发展为去势抵抗性。最近的数据表明，免疫细胞参与了这种去势抵抗性前列腺癌（CRPC）的发展。特别是，在雄激素剥夺后不久，在 PCa 患者和小鼠模型中均发现 T 细胞扩增。然而，在 CRPC 发展过程中，哪种 T 细胞亚群发挥重要作用尚不清楚。在这里，我们鉴定了一组新型的 CD4HLA-G T 细胞，这些细胞在 ADT 后 PCa 患者中经历了显著扩增。在小鼠 PCa 模型中，在 CRPC 早期阶段也会扩增类似的 CD4 T 细胞群。这些细胞被鉴定为表达 IL-4 的 T17 细胞，并且与患者的 CRPC 发病以及在小鼠模型中 CRPC 的发展有关。从机制上讲，CD4HLA-G T 细胞通过调节 CD11bF4/80 巨噬细胞的活性和迁移来驱动前列腺癌细胞的雄激素非依赖性生长。此外，在雄激素剥夺后，升高的 PGE-EP2 信号通过上调 IL23R 抑制了胸腺细胞中 CD4 的表达，随后诱导 CD4 幼稚 T 细胞向表达 IL-4 的 T17 表型极化。在治疗上，当 CD4HLA-G T 细胞出现但不在雄激素剥夺后立即用塞来昔布灭活 PGE 信号时，可显著抑制 CRPC 的发生。总之，我们的研究结果表明，一种异常的 CD4HLA-G T 细胞群对于 CRPC 的发展是必不可少的，并为联合 ADT 和 PGE 抑制治疗前列腺癌提供了一种新的治疗途径。
