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Lineage tracking reveals dynamic relationships of T cells in colorectal cancer

Nature (2018) | Download Citation

Abstract

T cells are key elements of cancer immunotherapy1, but certain fundamental properties, such as development and migration of T cells within tumours, remain elusive. The enormous T cell receptor (TCR) repertoire, which is required for recognising 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 (CRC) and developed STARTRAC (single T-cell analysis by RNA-seq and TCR tracking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While 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, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+BHLHE40+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable responses to immune-checkpoint blockade. Furthermore, IGFLR1 was highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provide a powerful avenue to comprehensively dissect the T cell properties in CRC, which could provide new insights into the dynamic relationships of T cells in other cancers.

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Author information

Author notes

  1. These authors contributed equally: Lei Zhang, Xin Yu, Liangtao Zheng, Yuanyuan Zhang.

Affiliations

  1. Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China

    • Lei Zhang
    • , Liangtao Zheng
    • , Qiao Fang
    •  & Zemin Zhang
  2. Department of Inflammation and Oncology, Discovery Research, Amgen Inc., South San Francisco, CA, 94080, USA

    • Xin Yu
    • , Julie Y. Huang
    • , Hiroyasu Konno
    •  & Wenjun Ouyang
  3. BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China

    • Yuanyuan Zhang
    • , Ranran Gao
    • , Boxi Kang
    • , Qiming Zhang
    • , Xinyi Guo
    • , Xueda Hu
    • , Xianwen Ren
    •  & Zemin Zhang
  4. Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing, 100044, China

    • Yansen Li
    • , Yingjiang Ye
    • , Shan Wang
    •  & Zhanlong Shen
  5. Department of Pathology, Peking University People’s Hospital, Beijing, 100044, China

    • Songyuan Gao

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Correspondence to Zhanlong Shen or Wenjun Ouyang or Zemin Zhang.

Supplementary information

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    This file contains Supplementary Tables 1-11 and a Supplementary Table Guide.

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DOI

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

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