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

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.

• Authors: Kathryn E Yost, Ansuman T Satpathy, Daniel K Wells, Yanyan Qi, Chunlin Wang, Robin Kageyama, Katherine L McNamara, Jeffrey M Granja, Kavita Y Sarin, Ryanne A Brown, Rohit K Gupta, Christina Curtis, Samantha L Bucktrout, Mark M Davis, Anne Lynn S Chang, Howard Y Chang
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 8 Pg. 1251-1259 (08 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 31359002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell
• T Cell Transcription Factor 1
• TCF7 protein, human

Topics

• Carcinoma, Basal Cell (drug therapy, immunology)
• Carcinoma, Squamous Cell (drug therapy, immunology)
• Humans
• Immunotherapy
• Lymphocytes, Tumor-Infiltrating (immunology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Receptors, Antigen, T-Cell (physiology)
• Sequence Analysis, RNA
• T Cell Transcription Factor 1 (physiology)
• T-Lymphocytes (immunology)