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

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

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 microenvi...

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Main Authors: Diane Damotte, Laurence Zitvogel, Marco Alifano, Marie-Caroline Dieu-Nosjean, Gabriela Bindea, Jeremy Goc, Jules Russick, Pierre-Emmanuel Joubert, Mélanie Gillard-Bocquet, Carine Torset, Maxime Meylan, Florent Petitprez, Marie-Agnes Dragon-Durey, Solenne Marmier, Aditi Varthaman, Nathalie Josseaume, Claire Germain, Pierre Validire, Ludovic Fournel, Audrey Lupo, Isabelle Cremer
Format: Article
Language:English
Published: BMJ Publishing Group 2020-10-01
Series:Journal for ImmunoTherapy of Cancer
Online Access:https://jitc.bmj.com/content/8/2/e001054.full
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Summary: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.
ISSN:2051-1426

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