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

2019; Nature Portfolio; Volume: 25; Issue: 8 Linguagem: Inglês

10.1038/s41591-019-0522-3

1546-170X

Kathryn E. Yost, Ansuman T. Satpathy, Daniel K. Wells, Yanyan Qi, Chunlin Wang, Robin Kageyama, Katherine McNamara, Jeffrey M. Granja, Kavita Y. Sarin, Ryanne A. Brown, Rohit Gupta, Christina Curtis, Samantha Bucktrout, Mark M. Davis, Anne Lynn S. Chang, Howard Y. Chang,

Immune Cell Function and Interaction

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. Following anti-PD-1 therapy in patients with basal or squamous cell carcinoma, the CD8+ T cell response largely consists of an expanded and exhausted repertoire of new T cell clones.