Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

• Published in: Journal for immunotherapy of cancer Vol. 8; no. 2; p. e001054
• Main Authors: Russick, Jules, Joubert, Pierre-Emmanuel, Gillard-Bocquet, Mélanie, Torset, Carine, Meylan, Maxime, Petitprez, Florent, Dragon-Durey, Marie-Agnes, Marmier, Solenne, Varthaman, Aditi, Josseaume, Nathalie, Germain, Claire, Goc, Jérémy, Dieu-Nosjean, Marie-Caroline, Validire, Pierre, Fournel, Ludovic, Zitvogel, Laurence, Bindea, Gabriela, Lupo, Audrey, Damotte, Diane, Alifano, Marco, Cremer, Isabelle
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 16.10.2020; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Basic Tumor Immunology; biomarkers; Biomarkers, Tumor; Cancer; Chemokines; Cloning; CTLA-4 antigen; Cytotoxicity; Flow cytometry; Gene expression; Hospitals; Humans; Immunotherapy; Killer Cells, Natural; Life Sciences; Ligands; Lung cancer; lung neoplasms; Lymphocytes; Natural Killer T-Cells; Software; Thoracic surgery; Transcriptome; tumor; Tumor Microenvironment; Tumor necrosis factor-TNF; France; United States > US; California; CTLA-4 antigen; tumor microenvironment; lung neoplasms; biomarkers; tumor; Natural Killer T-Cells
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-001054

BackgroundNatural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype.ObjectiveWe aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME.MethodsNK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs.ResultsIn the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8+ T cells in NSCLC.ConclusionsThese findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.