雄激素剥夺治疗对前列腺癌免疫微环境影响的多层级研究

A multi-level study of androgen deprivation therapy on the immune microenviron- ment in prostate cancer

摘要

目的：从免疫水平、动物模型转录组及单细胞组学层面系统评估雄激素剥夺治疗（androgen deprivation therapy，ADT）对前列腺癌免疫微环境的影响，阐明 ADT 介导的肿瘤免疫重塑特征。方法：纳人北京大学人民医院接受 ADT 治疗的前列腺癌患者 12 例，动态检测血清前列腺特异性抗原（prostate specific antigen，PSA）、睾酮水平、外周血免疫细胞比例与细胞因子表达变化；从基因表达汇编（gene expression omnibus，GEO）数据库下载前列腺癌人源肿瘤异种移植（patient-derived tumor xenograft，PDX）模型去势前后转录组数据（GSE41193，共5例），进行相关生物信息学分析；另对4例前列腺癌组织（2 例接受 ADT 新辅助治疗、2 例未接受）行单细胞 RNA 测序（single-cellRNA sequencing，scRNA-seq），解析肿瘤微环境细胞组成及 T 细胞功能状态。结果：ADT 显著降低患者血清 PSA 及睾酮水平，但外周血免疫细胞比例及大多数细胞因子无明显影响。PDX 模型分析显示，前列腺癌患者去势后差异表达基因富集于神经相关及免疫调控通路，多种免疫细胞浸润特征呈现趋势性改变。scRNA-seq 结果表明，ADT 治疗后肿瘤内效应性 CD8⁺T 细胞比例下降，GZMA、GZMB、GNLY、NKG7 等细胞毒相关基因表达下调，而调节性 T 细胞（Treg）相对富集。Hallmark 通路分析显示干扰素信号通路受到抑制。结论：ADT 可诱导前列腺癌肿瘤免疫微环境发生趋势性的改变，表现为 T 细胞杀伤功能减弱及免疫抑制性细胞富集，提示 ADT 可能促进抑制性肿瘤免疫微环境（tumor immune microenvironment，TIME）形成，为 ADT 联合免疫调节治疗策略提供了理论依据。

Abstract

Objective：To systematically evaluate the impact of androgen deprivation therapy（ADT） on the immune microenvironment of prostate cancer at the levels of systemic immunity，animal model transcriptomics，and single-cell omics，and to elucidate the characteristics of ADT-mediated tumor im- mune remodeling. Methods：Twelve prostate cancer patients who received ADT at Peking University People＇s Hospital were enrolled.Dynamic monitoring of serum prostate specific antigen（PSA）， testosterone levels，peripheral blood immune cell proportions，and cytokine expression changes was performed. Transcriptomic data from patient-derived tumor xenograft（PDX）models before and after castration （GSE41193， 5 cases in total）were downloaded from the gene expression omnibus（GEO）database for relevant bioinformatics analyses.Single-cell RNA sequencing（scRNA-seq）was performed on 4 prostate cancer tissue samples（2 received neoadjuvant ADT， 2 untreated）to analyze tumor microenvironment cell composition and T-cell functional states. Results：ADT significantly reduced serum PSA and testosterone levels in the patients，but had no significant effect on peripheral blood immune cell proportions or most cytokines.PDX model analysis showed that differentially expressed genes after castration were enriched in neural-related and immune regulation pathways，with trending changes observed in the infiltration charac- teristics of various immune cells.scRNA-seq results indicated a decreased proportion of intratumoral ef- fector CD8  ⁺T cells after ADT treatment，with downregulated expression of cytotoxicity-related genes， such as GZMA,GZMB,GNLY ，and NKG7 ，while regulatory T cells（Tregs）were relatively enriched. Hallmark pathway analysis revealed suppression of interferon signaling pathways. Conclusion：The pre- liminary results of this study suggest that ADT can induce a trend of change in the tumor immune micro-environment of prostate cancer，characterized by weakened T-cell killing function and enrichment of im- munosuppressive cells.This suggests that ADT may promote the formation of an immunosuppressive tumor immune microenvironment（TIME），providing a theoretical basis for ADT combined with immune- modulating therapeutic strategies.

关键词

前列腺癌 / 雄激素剥夺治疗 / 肿瘤免疫微环境

Key words

Prostate cancer / Androgen deprivation therapy / Tumor immune microenvironment

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基金资助

国家自然科学基金(82371840)

北京市自然科学基金(7262134)