Department of Inflammation and Oncology, Amgen Research, Amgen, South San Francisco, CA.
Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, China.
J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20201329.
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.
单细胞 RNA 测序是一种强大的工具，可用于研究人类癌症和动物模型中的细胞异质性、新型标志物和靶基因以及治疗机制。在这里，我们通过基于 PCA 的亚聚类分析和使用 STARTRAC 算法的 TCR 追踪分析了从多个小鼠肿瘤模型中获得的 T 细胞的单细胞 RNA 测序数据。这种方法揭示了各种不同的 T 细胞亚群和激活状态，以及人类和小鼠肿瘤之间 T 细胞亚群的对应关系。STARTRAC 分析表明，外周 T 细胞亚群与肿瘤浸润的 CD8+细胞、CD4+Th1 细胞和 Treg 细胞在发育上有关联。此外，大量配对的 TCRα/β 序列使我们能够识别肿瘤中特定的配对公共 TCR 克隆富集。最后，我们确定 CCR8 是一种与肿瘤相关的 Treg 细胞标志物，它可以优先耗尽肿瘤相关的 Treg 细胞。我们表明，CCR8 耗竭抗体治疗在 CT26 肿瘤中提供了治疗益处，并与 MC38 和 B16F10 肿瘤模型中的抗 PD-1 治疗具有协同作用。
