Single-Cell Transcriptome Analysis Reveals Intratumoral Heterogeneity in ccRCC, which Results in Different Clinical Outcomes
Single-Cell Transcriptome Analysis Reveals Intratumoral Heterogeneity in ccRCC, which Results in Different Clinical Outcomes
复制标题
单细胞转录组分析揭示 ccRCC 瘤内异质性，从而导致不同的临床结果
DOI：
10.1016/j.ymthe.2020.04.023
复制
发表时间：
2020-07-08
影响因子：
12.4
通讯作者：
Chen, Ke
中科院分区：
文献类型：
--
作者：
Hu, Junyi;Chen, Zhaohui;Chen, Ke
肾透明细胞癌(CcRCC)是最常见的肾癌组织学类型。为了研究ccRCC的瘤内异质性，我们分析了单细胞RNA测序数据，鉴定了15种主要细胞类型，以及来自肿瘤或非恶性组织的39种细胞亚群，并通过组织芯片的免疫荧光染色证实了它们的存在。在这项研究中，我们证实T细胞耗竭是导致肾细胞癌组织免疫抑制特性的关键因素，而免疫抑制特性与预后不良密切相关。我们还发现，异常代谢模式不仅发生在癌细胞中，也发生在肿瘤浸润性基质细胞中。根据CIBERSORTx检测到的每个细胞团的比例，来自癌症基因组图谱(TCGA)KIRC数据集的533名患者被分为三组。其中一组患者的CD8(+)活化细胞比例较低，而CD8(+)细胞耗尽的比例较高，这与预后不良有关。因此，阻断免疫抑制检查点，不仅是PD-1，也包括LAG3、TIM-3和其他抑制性检查点，可能成为ccRCC免疫治疗的潜在靶点。我们的工作将进一步加深对ccRCC组织间异质性的理解，并为ccRCC的治疗提供新的策略。
Clear-cell renal cell carcinoma (ccRCC) is the most common histological type of RCC. To investigate the intratumoral heterogeneity of ccRCC, we analyzed single-cell RNA-sequencing data and identified 15 major cell types, along with 39 subgroups of cells derived from tumor or non-malignant tissues, and confirmed their presence by immunofluorescence staining in tissue chips. In this study, we verified that T cell exhaustion was the key factor responsible for the immunosuppressive property of ccRCC tissues, which was significantly related to poor prognosis. We also found that abnormal metabolic patterns occurred not only in cancer cells, but also in tumor-infiltrating stromal cells. Based on the fraction of each cell cluster detected by CIBERSORTx, 533 patients from The Cancer Genome Atlas (TCGA) KIRC dataset were divided into three groups. One group, which showed a lesser proportion of activated CD8(+) cells and greater proportion of exhausted CD8(+) cells, was associated with a poor prognosis. Hence, the blockade of immunosuppressive checkpoints, not only PD-1, but also LAG3, TIM-3, and other inhibitory checkpoints, could serve as a potential target for ccRCC immunotherapy. Our work will further the understanding of the heterogeneity among ccRCC tissues and provide novel strategies for treating ccRCC.