去势抵抗性前列腺癌中的周细胞与疾病进展和免疫治疗反应相关：单细胞分析的见解

Pericytes in castration-resistant prostate cancer associated with disease progression and immunotherapy response: insights from single-cell analysis.

作者信息

Qiu Yifeng, Wang Yuhan, Liu Jiahe, Sun Kai, Horie Shigeo, Bing Zhitong, Hou Qi

机构信息

Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen University Medical School, Shenzhen, 518060, China.

Department of Urology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China.

出版信息

Cancer Cell Int. 2025 Jun 3;25(1):200. doi: 10.1186/s12935-025-03838-3.

DOI:10.1186/s12935-025-03838-3

PMID:40462105

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12135593/

Abstract

BACKGROUND

The current immunotherapeutic strategies yield limited therapeutic benefits in patients with castration-resistant prostate cancer (CRPC) due to its immunologically "cold" tumor milieu. Pericytes play a pivotal role in facilitating metastatic dissemination and modulating immune response in malignancies. Our investigation is designed to decipher the biological effects of pericytes on CRPC and their interactions with the tumor microenvironment.

METHODS

We leveraged single-cell transcriptomics and immunofluorescence staining to ascertain the presence and spatial distribution of pericytes in prostate cancer (PCa). Subsequently, we thoroughly delineated the phenotypic and functional characteristics of the CRPC-pericytes subpopulation. The clinical and prognostic significance of CRPC-pericytes was assessed by employing several bulk RNA-seq and microarray datasets. Additionally, we examined the association between the abundance of CRPC-pericytes and immunological features in the PCa microenvironment. Furthermore, the RM-1 subcutaneous tumor model was leveraged to assess the synergistic efficacy of platelet-derived growth factor (PDGF) signaling inhibition in conjunction with immunotherapeutic interventions.

RESULTS

We discerned pericytes according to their marker genes and observed the α-SMA-positive pericytes encircling the vasculature in PCa and adjacent normal tissues. In the CRPC-pericytes subpopulation, a pronounced upregulation of PDGF signaling and angiogenesis was observed, whereas antitumor immunity-related pathways were suppressed. In addition, CRPC-pericytes displayed notably enhanced interactions with endothelial cells, fibroblasts, and myeloid cells, compared to PCa-pericytes. Patients with elevated prevalence of CRPC-pericytes exhibited notably reduced recurrence-free survival and unresponsiveness to immunotherapeutic interventions. Moreover, CRPC-pericytes were positively associated with immunosuppressive properties of the TME. Notably, combinatorial application of PDGFR inhibitor and anti-PD-1 therapy elicited substantial synergistic antitumor effects in murine PCa models.

CONCLUSION

Our investigation uncovers a CRPC-pericytes subpopulation implicated in cancer progression and immunosuppression, suggesting that therapies targeting the phenotypic transition of pericytes could act synergistically with immunotherapeutic regimens to improve survival rates in CRPC.

摘要

背景

由于去势抵抗性前列腺癌（CRPC）患者的肿瘤微环境呈免疫“冷”状态，目前的免疫治疗策略在这些患者中产生的治疗益处有限。周细胞在促进恶性肿瘤的转移扩散和调节免疫反应中起关键作用。我们的研究旨在阐明周细胞对CRPC的生物学作用及其与肿瘤微环境的相互作用。

方法

我们利用单细胞转录组学和免疫荧光染色来确定前列腺癌（PCa）中周细胞的存在和空间分布。随后，我们全面描述了CRPC-周细胞亚群的表型和功能特征。通过使用几个批量RNA测序和微阵列数据集评估了CRPC-周细胞的临床和预后意义。此外，我们研究了CRPC-周细胞丰度与PCa微环境中免疫特征之间的关联。此外，利用RM-1皮下肿瘤模型评估血小板衍生生长因子（PDGF）信号抑制与免疫治疗干预联合使用的协同疗效。

结果

我们根据其标记基因识别出周细胞，并观察到α-SMA阳性周细胞环绕PCa和相邻正常组织中的血管。在CRPC-周细胞亚群中，观察到PDGF信号传导和血管生成明显上调，而抗肿瘤免疫相关途径受到抑制。此外，与PCa-周细胞相比，CRPC-周细胞与内皮细胞、成纤维细胞和髓样细胞的相互作用明显增强。CRPC-周细胞患病率升高的患者无复发生存率明显降低，且对免疫治疗干预无反应。此外，CRPC-周细胞与肿瘤微环境的免疫抑制特性呈正相关。值得注意的是，PDGFR抑制剂和抗PD-1疗法的联合应用在小鼠PCa模型中产生了显著的协同抗肿瘤作用。