Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Oncol Res. 2023 Jun 27;31(4):591-604. doi: 10.32604/or.2023.029282. eCollection 2023.
Ovarian cancer (OV) is highly heterogeneous tumor with a very poor prognosis. Studies increasingly show that T cell exhaustion is prognostically relevant in OV. The aim of this study was to dissect the heterogeneity of T cell subclusters in OV through single cell transcriptomic analysis. The single RNA-sequencing (scRNA-seq) data of five OV patients were analyzed, and six major cell clusters were identified after threshold screening. Further clustering of T cell-associated clusters revealed four subtypes. Pathways related to oxidative phosphorylation, G2M checkpoint, JAK-STAT and MAPK signaling were significantly activated, while the p53 pathway was inhibited in the CD8+ exhausted T cells. The standard marker genes of CD8+ T cell exhaustion were screened to develop a T-cell related gene score (TRS) based on random forest plots in TCGA cohort. The patients with low TRS have better prognosis compared to the patients with high TRS in both TCGA and GEO. In addition, most genes included in the TRS showed significant differences in expression levels between the high- and low-risk groups. Immune cell infiltration was analyzed using the MCPcounter and xCell algorithms, which revealed significant differences between the two risk groups, indicating that the different prognoses may stem from the respective immune landscapes. In addition, CD38 knockdown in OV cell lines increased apoptosis and inhibited invasion . Finally, we performed a drug sensitivity analysis and identified six potential drug candidates for OV. To summarize, we identified the heterogeneity and clinical significance of T cell exhaustion in OV and built a superior prognostic model based on T cell exhaustion genes, which can contribute to the development of more precise and effective therapies.
卵巢癌（OV）是一种高度异质性肿瘤，预后极差。越来越多的研究表明，T 细胞耗竭与 OV 的预后相关。本研究旨在通过单细胞转录组分析剖析 OV 中 T 细胞亚群的异质性。分析了五名 OV 患者的单细胞 RNA 测序（scRNA-seq）数据，经过阈值筛选后确定了六个主要的细胞簇。进一步对与 T 细胞相关的簇进行聚类，揭示了四个亚型。与氧化磷酸化、G2M 检查点、JAK-STAT 和 MAPK 信号通路相关的途径显著激活，而 p53 途径在 CD8+耗竭 T 细胞中受到抑制。筛选出 CD8+T 细胞耗竭的标准标记基因，基于 TCGA 队列中的随机森林图构建基于 T 细胞相关基因评分（TRS）。与高 TRS 相比，TCGA 和 GEO 中的低 TRS 患者具有更好的预后。此外，TRS 中包含的大多数基因在高低风险组之间的表达水平存在显著差异。使用 MCPcounter 和 xCell 算法分析免疫细胞浸润，结果显示两组之间存在显著差异，表明不同的预后可能源于各自的免疫景观。此外，在 OV 细胞系中敲低 CD38 可增加细胞凋亡并抑制侵袭。最后，我们进行了药物敏感性分析，确定了六个卵巢癌的潜在药物候选物。总之，我们鉴定了 OV 中 T 细胞耗竭的异质性和临床意义，并基于 T 细胞耗竭基因构建了一个优越的预后模型，这有助于开发更精确和有效的治疗方法。
