Analyzing single-cell transcriptome and TCR sequences from 12 colorectal cancer patients, Zhang, Yu, Zheng, and Zhang et al. categorized T cell subsets by unbiased clustering and phenotyping by localization, migration, and proliferation. A TCR clonotype-dependent developmental lineage linked CD8+ effector memory cells to recently activated effector memory and exhausted T cells (TEX). Microsatellite-unstable tumors were enriched in a clonally expanded and proliferative CXCL13+ BHLHE40+ Th1-like CD4+ T cell subset with upregulated IGFLR1, which was also upregulated in TEX . In vitro experiments suggested a role of IGFLR1 in TCR costimulation.
T cells are key elements of cancer immunotherapy(1), 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-antigens(2), could serve as lineage tags to track these T cells in tumours(3). 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-gamma-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.
Author Info: (1) Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China. (2) Department of Inflammation and Oncolog
Author Info: (1) Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China. (2) Department of Inflammation and Oncology, Discovery Research, Amgen Inc., South San Francisco, CA, 94080, USA. (3) Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China. (4) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (5) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, China. (6) Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China. (7) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (8) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (9) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (10) Department of Inflammation and Oncology, Discovery Research, Amgen Inc., South San Francisco, CA, 94080, USA. (11) Department of Inflammation and Oncology, Discovery Research, Amgen Inc., South San Francisco, CA, 94080, USA. (12) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (13) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, China. (14) Department of Pathology, Peking University People's Hospital, Beijing, 100044, China. (15) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, China. (16) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (17) BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. (18) Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, 100044, China. shenlong1977@163.com. (19) Department of Inflammation and Oncology, Discovery Research, Amgen Inc., South San Francisco, CA, 94080, USA. wouyang@amgen.com. (20) Beijing Advanced Innovation Centre for Genomics, Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing, 100871, China. zemin@pku.edu.cn. BIOPIC and School of Life Sciences, Peking University, Beijing, 100871, China. zemin@pku.edu.cn.
