恩杂鲁胺治疗前列腺癌时出现雄激素受体阻断耐药会导致肿瘤免疫微环境发生免疫抑制改变。
Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment.
机构信息
Department of Urologic Surgery, University of California Davis, Sacramento, California, USA.
Flow Cytometry Core, University of California Davis, Sacramento, California, USA.
出版信息
J Immunother Cancer. 2023 May;11(5). doi: 10.1136/jitc-2022-006581.
BACKGROUND
Emerging data suggest that patients with enzalutamide-treated prostate cancer with increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 clinical trial revealed that the combination of atezolizumab (a PD-L1 inhibitor) and enzalutamide failed to extend overall survival in patients with castration-resistant prostate cancer (CRPC). However, the mechanisms underlying treatment failure remain unknown.
METHODS
Human CRPC C4-2B cells and murine Myc-CaP cells were chronically exposed to increasing concentrations of enzalutamide and the cells resistant to enzalutamide were referred to as C4-2B MDVR and Myc-CaP MDVR, respectively. The mechanisms of action in drug-resistant prostate cancer cells were determined using RNA sequencing analyses, RNA interference, real-time PCR, western blotting, and co-culturing technologies. Myc-CaP and Myc-CaP MDVR tumors were established in syngeneic FVB mice, and tumor-infiltrating leukocytes were isolated after enzalutamide treatment. The stained immune cells were determined by flow cytometry, and the data were analyzed using FlowJo.
RESULTS
Immune-related signaling pathways (interferon alpha/gamma response, inflammatory response, and cell chemotaxis) were suppressed in human enzalutamide-resistant prostate cancer cells. PD-L1 was overexpressed and negatively regulated by androgen receptor signaling in resistant cells and patient with CRPC cohorts. Enzalutamide treatment decreased CD8 T-cell numbers but increased monocytic myeloid-derived suppressor cell (M-MDSC) populations and PD-L1 expression within murine Myc-CaP tumors. Similarly, chemotaxis and immune response-regulating signaling pathways were suppressed, and PD-L1 expression was also increased using enzalutamide-resistant Myc-CaP MDVR cells. Notably, MDSC populations were significantly increased in Myc-CaP MDVR orthotopic tumors compared with those in Myc-CaP parental tumors. Co-culturing bone marrow cells with Myc-CaP MDVR cells significantly promoted MDSC differentiation and shifted towards M2 macrophage skewing.
CONCLUSIONS
Our study suggests that immunosuppressive signaling can be promoted directly by enzalutamide-resistant prostate cancer cells and may be a potential means by which the efficacy of immune checkpoint inhibitors in enzalutamide-resistant prostate cancer is diminished.
背景
新出现的数据表明，接受恩扎卢胺治疗的前列腺癌患者中，程序性死亡配体 1（PD-L1）表达增加者可能从抗 PD-L1 治疗中获益。不幸的是，III 期 IMbassador250 临床试验显示，阿替利珠单抗（一种 PD-L1 抑制剂）与恩扎卢胺联合治疗未能延长去势抵抗性前列腺癌（CRPC）患者的总生存期。然而，治疗失败的机制尚不清楚。
方法
将人 CRPC C4-2B 细胞和鼠 Myc-CaP 细胞长期暴露于逐渐增加的恩扎卢胺浓度下，对恩扎卢胺耐药的细胞分别称为 C4-2B MDVR 和 Myc-CaP MDVR。使用 RNA 测序分析、RNA 干扰、实时 PCR、Western blot 和共培养技术确定耐药前列腺癌细胞中的作用机制。在同基因 FVB 小鼠中建立 Myc-CaP 和 Myc-CaP MDVR 肿瘤，并在恩扎卢胺治疗后分离肿瘤浸润性白细胞。通过流式细胞术测定染色免疫细胞，并用 FlowJo 进行数据分析。
结果
在人恩扎卢胺耐药前列腺癌细胞中，免疫相关信号通路（干扰素 α/γ 反应、炎症反应和细胞趋化）受到抑制。在耐药细胞和 CRPC 患者队列中，PD-L1 过表达并受雄激素受体信号负调控。恩扎卢胺治疗降低了 CD8 T 细胞数量，但增加了鼠 Myc-CaP 肿瘤中的单核细胞髓系来源抑制细胞（M-MDSC）群体和 PD-L1 表达。同样，用恩扎卢胺耐药 Myc-CaP MDVR 细胞处理时，趋化和免疫反应调节信号通路受到抑制，PD-L1 表达也增加。值得注意的是，与 Myc-CaP 亲本肿瘤相比，Myc-CaP MDVR 原位肿瘤中的 MDSC 群体显著增加。骨髓细胞与 Myc-CaP MDVR 细胞共培养可显著促进 MDSC 分化并向 M2 巨噬细胞倾斜。
结论
我们的研究表明，免疫抑制信号可直接由恩扎卢胺耐药前列腺癌细胞促进，这可能是免疫检查点抑制剂在恩扎卢胺耐药前列腺癌中疗效降低的潜在手段。
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