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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinoma, Basal Cell / drug therapy*
  • Carcinoma, Basal Cell / immunology
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / 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*

Substances

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