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Nat Med. 2019 Aug;25(8):1251-1259. doi: 10.1038/s41591-019-0522-3. Epub 2019 Jul 29.

Clonal replacement of tumor-specific T cells following PD-1 blockade.

Yost KE1, Satpathy AT2,3,4, Wells DK5, Qi Y1, Wang C6, Kageyama R5, McNamara KL7,8,9, Granja JM1,8,10, Sarin KY11, Brown RA12,11, Gupta RK13, Curtis C7,8,9, Bucktrout SL5, Davis MM5,14,15,16, Chang ALS17, Chang HY18,19,20,21,22.

Author information

1
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
2
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. satpathy@stanford.edu.
3
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. satpathy@stanford.edu.
4
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. satpathy@stanford.edu.
5
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
6
iRepertoire Inc, Huntsville, AL, USA.
7
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.
8
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
9
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
10
Program in Biophysics, Stanford University School of Medicine, Stanford, CA, USA.
11
Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
12
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
13
Stanford Biobank, Stanford University School of Medicine, Palo Alto, CA, USA.
14
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
15
Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
16
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
17
Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA. alschang@stanford.edu.
18
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
19
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. howchang@stanford.edu.
20
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
21
Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA. howchang@stanford.edu.
22
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.

Abstract

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. 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 unclear2-4. 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.

PMID:
31359002
PMCID:
PMC6689255
[Available on 2020-01-29]
DOI:
10.1038/s41591-019-0522-3

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