生物
CD8型
细胞毒性T细胞
效应器
T细胞受体
T细胞
免疫系统
转录组
细胞生物学
癌症研究
免疫学
遗传学
基因
基因表达
体外
作者
Lei Zhang,Xin Yu,Liangtao Zheng,Yuanyuan Zhang,Yansen Li,Fang Qiao,Ranran Gao,Boxi Kang,Qiming Zhang,Julie Y. Huang,Hiroyasu Konno,Xinyi Guo,Yingjiang Ye,Songyuan Gao,Shan Wang,Xueda Hu,Xianwen Ren,Zhanlong Shen,Wenjun Ouyang
出处
期刊:Nature
[Springer Nature]
日期:2018-10-29
卷期号:564 (7735): 268-272
被引量:720
标识
DOI:10.1038/s41586-018-0694-x
摘要
T cells are key elements of cancer immunotherapy1 but certain fundamental properties, such as the development and migration of T cells within tumours, remain unknown. The enormous T cell receptor (TCR) repertoire, which is required for the recognition of foreign and self-antigens2, could serve as lineage tags to track these T cells in tumours3. Here we obtained transcriptomes of 11,138 single T cells from 12 patients with colorectal cancer, and developed single T cell analysis by RNA sequencing and TCR tracking (STARTRAC) indices to quantitatively analyse the dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. Although both CD8+ effector and ‘exhausted’ T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, most tumour-infiltrating T regulatory (Treg) cells showed clonal exclusivity, whereas certain Treg cell clones were developmentally linked to several T helper (TH) cell clones. Notably, we identified two IFNG+ TH1-like cell clusters in tumours that were associated with distinct IFNγ-regulating transcription factors —the GZMK+ effector memory T cells, which were associated with EOMES and RUNX3, and CXCL13+BHLHE40+ TH1-like cell clusters, which were associated with BHLHE40. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in patients with microsatellite-instable tumours, and this might explain their favourable responses to immune-checkpoint blockade. Furthermore, IGFLR1 was highly expressed in both CXCL13+BHLHE40+ TH1-like cells and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provide a powerful approach to dissect the T cell properties in colorectal cancer comprehensively, and could provide insights into the dynamic relationships of T cells in other cancers. An integrated RNA-sequencing approach demonstrates that CXCL13+ TH1-like cells are preferentially enriched in microsatellite-instable tumours from patients with colorectal cancer, and IGFLR1 is identified as a co-stimulatory molecule.
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