Sophie Guia, Aurore Fenis, Camille Baudesson De Chanville, Justine Galluso, Hakim Medjouel, Bertrand Escaliere, Angelika Modelska, Margaux Vienne, Noella Lopes, Amelie Pouchin, Benjamin Rossi, Laurent Gauthier, Sandrine Roulland, Eric Vivier, Emilie Narni-Mancinelli
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引用次数: 0
Abstract
Background: Natural killer (NK) cells exhibit potent cytotoxic activity against various cancer cell types. Over the past five decades, numerous methodologies have been employed to elucidate the intricate molecular mechanisms underlying NK cell-mediated tumor control. While significant progress has been made in elucidating the interactions between NK cells and tumor cells, the regulatory factors governing NK cell-mediated tumor cell destruction are not yet fully understood. This includes the diverse array of tumor ligands recognized by NK cells and the mechanisms that NK cells employ to eliminate tumor cells.
Methods: In this study, we employed a genome-wide CRISPR/Cas9 screening approach in conjunction with functional cytotoxicity assays to delineate the pathways modulating the susceptibility of colon adenocarcinoma HCT-116 cells to NK cell-mediated cytotoxicity.
Results: Analysis of guide RNA distribution in HCT-116 cells that survived co-incubation with NK cells identified ICAM-1 as a pivotal player in the NKp44-mediated immune synapse, with NKp44 serving as an activating receptor crucial for the elimination of HCT-116 tumor cells by NK cells. Furthermore, disruption of genes involved in the apoptosis or interferon (IFN)-γ signaling pathways conferred resistance to NK cell attack. We further dissected that NK cell-derived IFN-γ promotes mitochondrial apoptosis in vitro and exerts control over B16-F10 lung metastases in vivo.
Conclusion: Monitoring ICAM-1 levels on the surface of tumor cells or modulating its expression should be considered in the context of NK cell-based therapy. Furthermore, promoting FasL expression on the NK cell surface is reaffirmed as an important strategy to enhance NK cell-mediated tumor killing, offering an additional avenue for therapeutic optimization. Additionally, considering the diffusion properties of IFN-γ, our findings highlight the potential of leveraging NK cell-derived IFN-γ to enhance direct tumor cell killing and facilitate bystander effects via cytokine diffusion, warranting further investigation.
期刊介绍:
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.