State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.
Adv Sci (Weinh). 2023 Jun;10(17):e2206889. doi: 10.1002/advs.202206889. Epub 2023 Apr 24.
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.
人们高度关注雄激素受体 (AR) 作为驱动前列腺癌 (PCa) 上皮细胞生长的核心转录因子的作用。然而，人们对雄激素在 PCa 浸润免疫细胞中的作用以及雄激素剥夺疗法 (ADT) 的作用的理解仍很有限，ADT 是治疗晚期 PCa 的一线疗法。另一方面，免疫检查点阻断已彻底改变了某些癌症类型的治疗方法，但由于免疫抑制环境，在晚期 PCa 中并未取得任何获益。在这项研究中，据报道，AR 信号通路在小鼠和人类的 PCa 相关巨噬细胞 (TAMs) 中明显被激活。AR 在 TAMs 中充当 IL1B 的转录抑制因子。ADT 释放了 AR 对 IL1B 的抑制作用，从而导致 TAMs 中 IL-1β 的过度表达和分泌。IL-1β 诱导髓系来源的抑制细胞 (MDSCs) 聚集，抑制细胞毒性 T 细胞的激活，导致免疫抑制微环境。关键的是，抗 IL-1β 抗体与 ADT 和免疫检查点抑制剂抗 PD-1 抗体联合使用，在去势后对 PCa 具有更强的抗癌作用。总之，IL-1β 是晚期 PCa 的一个重要的雄激素反应性免疫治疗靶点。
