A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade

Nat Med. 2018 Jul;24(7):994-1004. doi: 10.1038/s41591-018-0057-z. Epub 2018 Jun 11.

Abstract

Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / ultrastructure
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Chemokine CXCL13 / metabolism
  • Chronic Disease
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism
  • Humans
  • Lipid Metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism*
  • T-Lymphocyte Subsets / immunology
  • Transcription, Genetic*
  • Virus Diseases / immunology

Substances

  • Chemokine CXCL13
  • Programmed Cell Death 1 Receptor
  • Glucose