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

• Published in: Nature medicine Vol. 24; no. 7; pp. 994 - 1004
• Main Authors: Thommen, Daniela S., Koelzer, Viktor H., Herzig, Petra, Roller, Andreas, Trefny, Marcel, Dimeloe, Sarah, Kiialainen, Anna, Hanhart, Jonathan, Schill, Catherine, Hess, Christoph, Savic Prince, Spasenija, Wiese, Mark, Lardinois, Didier, Ho, Ping-Chih, Klein, Christian, Karanikas, Vaios, Mertz, Kirsten D., Schumacher, Ton N., Zippelius, Alfred
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2018; Nature Publishing Group
• Subjects: 631/67/1612/1350; 631/67/327; 631/67/580; Animal models; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - ultrastructure; Chemokine CXCL13 - metabolism; Chronic Disease; Chronic infection; CXCL13 protein; Exhaustion; Gene Expression Regulation, Neoplastic; Glucose - metabolism; Humans; Immune system; Infectious Diseases; Lipid Metabolism; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Metabolic Diseases; Metabolism; Mitochondria - metabolism; Mitochondria - ultrastructure; Molecular Medicine; Neurosciences; Patients; PD-1 protein; Phenotype; Programmed Cell Death 1 Receptor - metabolism; T-Lymphocyte Subsets - immunology; Transcription; Transcription, Genetic; Tumors; Virus Diseases - immunology
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0057-z

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-1 T ), intermediate (PD-1 N ) and no PD-1 expression (PD-1 – ) from non-small-cell lung cancer patients. PD-1 T T cells showed a markedly different transcriptional and metabolic profile from PD-1 N and PD-1 – lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1 T 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-1 T 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. Tumor-infiltrating CD8 + T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.