Fan Lilv, Xu Guiliang, Cao Jingjing, Li Min, Zhang Huihui, Li Fanlin, Qi Xinyue, Zhang Xiaoqing, Li Zeyu, Han Ping, Yang Xuanming
Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
Cancers (Basel). 2021 Nov 8;13(21):5574. doi: 10.3390/cancers13215574.
Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among prostate cancer patients. Here, our aim was to ascertain the immune regulatory mechanisms involved in CRPC development and identify potential immunotherapies against CRPC.
A CRPC model was established using Myc-CaP cells in immune-competent FVB mice following castration. The immune cell profile of the tumor microenvironment (TME) was analyzed during CRPC development. Different immunotherapies were screened in the CRPC tumor model, and their efficacies and underlying mechanisms were investigated in vitro and in vivo.
During CRPC development, the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the TME increased. Among the immunotherapies tested, IFNα was more effective than anti-PD-L1, anti-CTLA-4, anti-4-1BB, IL-2, and IL-9 in reducing Myc-CaP CRPC tumor growth. IFNα reduced the number of G-MDSCs both in vitro during differentiation and in vivo in CRPC mice. Furthermore, IFNα reduced the suppressive function of G-MDSCs on T cell proliferation and activation.
G-MDSCs are crucial to effective immunotherapy against CRPC. Treatment with IFNα presents a promising therapeutic strategy against CRPC. Besides the direct inhibition of tumor growth and the promotion of T cell priming, IFNα reduces the number and the suppressive function of G-MDSCs and restores T cell activation.
转移性去势抵抗性前列腺癌（CRPC）是前列腺癌患者的主要死亡原因。在此，我们的目的是确定CRPC发生过程中涉及的免疫调节机制，并确定针对CRPC的潜在免疫疗法。
在去势后的免疫健全FVB小鼠中使用Myc-CaP细胞建立CRPC模型。在CRPC发生过程中分析肿瘤微环境（TME）的免疫细胞谱。在CRPC肿瘤模型中筛选不同的免疫疗法，并在体外和体内研究它们的疗效及潜在机制。
在CRPC发生过程中，TME中粒细胞髓源性抑制细胞（G-MDSCs）的比例增加。在所测试的免疫疗法中，IFNα在减少Myc-CaP CRPC肿瘤生长方面比抗PD-L1、抗CTLA-4、抗4-1BB、IL-2和IL-9更有效。IFNα在体外分化过程中和CRPC小鼠体内均减少了G-MDSCs的数量。此外，IFNα降低了G-MDSCs对T细胞增殖和活化的抑制功能。
G-MDSCs对CRPC的有效免疫治疗至关重要。IFNα治疗是一种有前景的CRPC治疗策略。除了直接抑制肿瘤生长和促进T细胞启动外，IFNα还减少了G-MDSCs的数量和抑制功能，并恢复了T细胞活化。
