Single-cell analysis reveals new evolutionary complexity in uveal melanoma
Single-cell analysis reveals new evolutionary complexity in uveal melanoma
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DOI：
10.1038/s41467-019-14256-1
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发表时间：
2020-01-24
影响因子：
16.6
通讯作者：
Harbour, J. William
中科院分区：
文献类型：
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作者：
Durante, Michael A.;Rodriguez, Daniel A.;Harbour, J. William
葡萄膜黑色素瘤（UM）是一种高度转移性癌症，与皮肤黑色素瘤相反，它对检查点免疫疗法基本上没有反应。在这里，我们使用来自8个原发性和3个转移性样本的59，915个肿瘤和非肿瘤细胞的scRNA-seq以单细胞分辨率询问肿瘤微环境。肿瘤细胞揭示了新的亚克隆基因组复杂性和转录状态。肿瘤浸润性免疫细胞包括以前未被识别的细胞类型多样性，包括主要表达检查点标记物LAG 3而不是PD 1或CTLA 4的CD 8（+）T细胞。V（D）J分析显示克隆扩增的T细胞，表明它们能够产生免疫应答。来自1B类UM的惰性肝转移被克隆扩增的浆细胞浸润，表明抗体介导的免疫。这种复杂的肿瘤和免疫细胞生态系统为UM生物学提供了新的见解，LAG 3被确定为高风险UM患者免疫检查点阻断的潜在候选者。葡萄膜黑色素瘤是高度转移性的，对检查点免疫疗法无反应。在这里，作者展示了8个原发性和3个转移性样本中59，915个细胞的单细胞转录组学，突出了肿瘤微环境的多样性。
Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8(+) T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM. Uveal melanoma is highly metastatic and unresponsive to checkpoint immunotherapy. Here, the authors present single-cell transcriptomics of 59,915 cells in 8 primary and 3 metastatic samples, highlighting the diversity of the tumour microenvironment.