Lineage tracking reveals dynamic relationships of T cells in colorectal cancer

Lei Zhang, Xin Yu, Liangtao Zheng, Yuanyuan Zhang, Yansen Li, Qiao Fang, 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 () and Zemin Zhang ()
Additional contact information
Lei Zhang: Peking University
Xin Yu: Discovery Research, Amgen
Liangtao Zheng: Peking University
Yuanyuan Zhang: Peking University
Yansen Li: Peking University People’s Hospital
Qiao Fang: Peking University
Ranran Gao: Peking University
Boxi Kang: Peking University
Qiming Zhang: Peking University
Julie Y. Huang: Discovery Research, Amgen
Hiroyasu Konno: Discovery Research, Amgen
Xinyi Guo: Peking University
Yingjiang Ye: Peking University People’s Hospital
Songyuan Gao: Peking University People’s Hospital
Shan Wang: Peking University People’s Hospital
Xueda Hu: Peking University
Xianwen Ren: Peking University
Zhanlong Shen: Peking University People’s Hospital
Wenjun Ouyang: Discovery Research, Amgen
Zemin Zhang: Peking University

Nature, 2018, vol. 564, issue 7735, 268-272

Abstract: Abstract 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.

Keywords: Treg Cells; MAIT Cells; Clonotypes; TEMRA Cells; Mucosal-associated Invariant T (MAIT) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (24)

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DOI: 10.1038/s41586-018-0694-x

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