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.

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.

• Authors: Daniela S Thommen, Viktor H Koelzer, Petra Herzig, Andreas Roller, Marcel Trefny, Sarah Dimeloe, Anna Kiialainen, Jonathan Hanhart, Catherine Schill, Christoph Hess, Spasenija Savic Prince, Mark Wiese, Didier Lardinois, Ping-Chih Ho, Christian Klein, Vaios Karanikas, Kirsten D Mertz, Ton N Schumacher, Alfred Zippelius
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 7 Pg. 994-1004 (07 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29892065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL13
• Programmed Cell Death 1 Receptor
• Glucose

Topics

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