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

Abstract

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.

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

“…The NK cell-cDC1 axis is integral for controlling immune responses to cancer and is linked to increased patient survival and/or responses to immunotherapies in metastatic melanoma, head and neck squamous cell carcinoma, triple negative breast cancer, and neuroblastoma ( 16 , 17 , 26 ). It is important to note that in certain tumor settings NK cells have been shown to have inhibitory effects on DC functions ( 50 – 52 ) and DCs can have inhibitory effects on NK cell functions [rev. in ( 44 – 47 )].…”

Hijacked Immune Cells in the Tumor Microenvironment: Molecular Mechanisms of Immunosuppression and Cues to Improve T Cell-Based Immunotherapy of Solid Tumors

“…The presence of NK cells in the TME correlates with good prognosis in breast cancer [ 73 ], gastrointestinal stromal tumors [ 74 ], neuroblastoma [ 75 ], prostate cancer, lung cancer [ 76 ], and in several other tumors [ 77 , 78 ]. Despite this positive correlation in several solid tumors, many studies have revealed that tumor-infiltrating NK cells have altered expression of inhibitory and activating receptors, and overexpression of exhaustion markers [ 79 , 80 ], and eventually, impaired activities [ 81 , 82 , 83 ]. Multiple factors of the immunosuppressive solid tumor environment contribute to their impaired functions in the TME.…”

“…One specific factor is the release of soluble NKG2D ligands by the tumor cells, which prevents interaction of NK cells with membrane-bound NKG2D ligands, thereby preventing their cytotoxic response [ 84 ]. Furthermore, in certain other tumors, there is either no or a negative correlation between the presence of NK cells and tumor progression [ 80 , 85 ]. Thus, a deeper understanding of NK cell functions in the TME, their phenotype, intercellular communication with other constituents of the TME, and the molecular constituents of the environment need to be further elucidated.…”

Potential Application of Plant-Based Functional Foods in the Development of Immune Boosters

“…NK cells are a type of immune cell closely related to responses during tumor formation, virus-associated infections, and immune regulation; they are the first line of defense in the human body (Russick et al, 2020). NK cells express several activation and inhibitory receptors, and secrete cytokines and chemokines to enable interaction with other immune cells (Vivier et al, 2018).…”