Lineage tracking reveals dynamic relationships of T cells in colorectal cancer
发布时间:2018/12/10 12:00:00

T cells are key elements ofcancerimmunotherapybut 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-antigens, could serve as lineage tags to track these T cells in tumours. Here we obtained transcriptomes of 11,138 single T cells from 12 patients with colorectalcancer, 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 Tregcell 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 colorectalcancercomprehensively, and could provide insights into the dynamic relationships of T cells in other cancers.

doi: 10.1038/s41586-018-0694-x.

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