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STARTRAC analyses of scRNAseq data from tumor models reveal T cell dynamics and therapeutic targets.

来自肿瘤模型的scRNAseq数据的STARTRAC分析揭示了T细胞动力学和治疗靶标。

  • 影响因子:9.83
  • DOI:10.1084/jem.20201329
  • 作者列表:"Bhatt D","Kang B","Sawant D","Zheng L","Perez K","Huang Z","Sekirov L","Wolak D","Huang JY","Liu X","DeVoss J","Manzanillo PS","Pierce N","Zhang Z","Symons A","Ouyang W
  • 发表时间:2021-06-07
Abstract

:Single-cell RNA sequencing is a powerful tool to examine cellular heterogeneity, novel markers and target genes, and therapeutic mechanisms in human cancers and animal models. Here, we analyzed single-cell RNA sequencing data of T cells obtained from multiple mouse tumor models by PCA-based subclustering coupled with TCR tracking using the STARTRAC algorithm. This approach revealed various differentiated T cell subsets and activation states, and a correspondence of T cell subsets between human and mouse tumors. STARTRAC analyses demonstrated peripheral T cell subsets that were developmentally connected with tumor-infiltrating CD8+ cells, CD4+ Th1 cells, and T reg cells. In addition, large amounts of paired TCRα/β sequences enabled us to identify a specific enrichment of paired public TCR clones in tumor. Finally, we identified CCR8 as a tumor-associated T reg cell marker that could preferentially deplete tumor-associated T reg cells. We showed that CCR8-depleting antibody treatment provided therapeutic benefit in CT26 tumors and synergized with anti-PD-1 treatment in MC38 and B16F10 tumor models.

摘要

: 单细胞RNA测序是在人类癌症和动物模型中检查细胞异质性、新型标志物和靶基因以及治疗机制的有力工具。在这里,我们通过基于PCA的子聚类与使用STARTRAC算法的TCR跟踪相结合,分析了从多个小鼠肿瘤模型获得的T细胞的单细胞RNA测序数据。该方法揭示了各种分化的T细胞亚群和活化状态,以及人与小鼠肿瘤之间的T细胞亚群的对应关系。STARTRAC分析显示外周T细胞亚群与肿瘤浸润的CD8 + 细胞、CD4 + Th1细胞和T reg细胞发育相关。此外,大量配对的TCR α/β 序列使我们能够鉴定肿瘤中配对的公共TCR克隆的特异性富集。最后,我们发现CCR8是一种肿瘤相关T reg细胞标志物,可以优先消耗肿瘤相关T reg细胞。我们发现CCR8-depleting抗体治疗在CT26肿瘤中提供治疗益处,并在MC38和B16F10肿瘤模型中与anti-PD-1治疗协同作用。

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