Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions. Issue 2 (16th October 2020)

• Record Type: Journal Article
• 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
• Is Part Of: Journal for immunotherapy of cancer. Volume 8:Issue 2(2020)
• Publication Date: 2020-10-16
• Subjects: CTLA-4 antigen -- Natural Killer T-Cells -- tumor microenvironment -- biomarkers -- tumor -- lung neoplasms; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-001054
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Natural 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. Objective: We 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. Methods: NK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs. Results: In 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. Conclusions: These findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.