期刊
NATURE MEDICINE
卷 25, 期 8, 页码 1251-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0522-3
关键词
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资金
- Parker Institute for Cancer Immunotherapy
- Michelson Foundation
- National Institutes of Health (NIH) [P50HG007735, R35CA209919, K08CA230188, K23CA211793, R01CA182514, DP1-CA238296, 5U19AI057229]
- National Science Foundation Graduate Research Fellowship Program (NSF) [DGE-1656518]
- Stanford Graduate Fellowship
- Bridge Scholar Award from Parker Institute for Cancer Immunotherapy
- Burroughs Wellcome Fund
- NIH [S10OD018220]
Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer(1). However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear(2-4). Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8(+)CD39(+) T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8(+) T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
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