去势抵抗性前列腺癌的周细胞与疾病进展和免疫治疗反应相关:来自单细胞分析的见解

IF 6 2区 医学 Q1 ONCOLOGY
Yifeng Qiu, Yuhan Wang, Jiahe Liu, Kai Sun, Shigeo Horie, Zhitong Bing, Qi Hou
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引用次数: 0

摘要

背景:目前的免疫治疗策略对去势抵抗性前列腺癌(CRPC)患者的治疗效果有限,因为其免疫“冷”肿瘤环境。在恶性肿瘤中,周细胞在促进转移传播和调节免疫反应中起着关键作用。我们的研究旨在破译周细胞对CRPC的生物学作用及其与肿瘤微环境的相互作用。方法: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。crpc -周细胞的临床和预后意义通过使用几个大量RNA-seq和微阵列数据集进行评估。此外,我们还研究了前列腺癌微环境中crpc -周细胞丰度与免疫学特征之间的关系。此外,利用RM-1皮下肿瘤模型来评估血小板衍生生长因子(PDGF)信号抑制与免疫治疗干预相结合的协同作用。结果:根据标记基因对周细胞进行识别,在前列腺癌及邻近正常组织中均有α- sma阳性周细胞包围血管。在crpc -周细胞亚群中,观察到PDGF信号和血管生成的显著上调,而抗肿瘤免疫相关途径被抑制。此外,与ca -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表现出明显降低的无复发生存率和对免疫治疗干预的无反应性。此外,crpc -周细胞与TME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治疗的联合应用在小鼠PCa模型中引起了大量的协同抗肿瘤作用。结论:我们的研究揭示了CRPC-周细胞亚群与癌症进展和免疫抑制有关,这表明针对周细胞表型转变的治疗可以与免疫治疗方案协同作用,提高CRPC患者的生存率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pericytes in castration-resistant prostate cancer associated with disease progression and immunotherapy response: insights from single-cell analysis.

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.

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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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