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IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction

Easom, NJW; Stegmann, KA; Swadling, L; Pallett, LJ; Burton, AR; Odera, D; Schmidt, N; ... Maini, MK; + view all (2018) IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction. Frontiers in Immunology , 9 , Article 1009. 10.3389/fimmu.2018.01009. Green open access

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Abstract

NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6+CD69+ liver-resident phenotype. Direct ex vivo staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by in vitro exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.

Type: Article
Title: IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2018.01009
Publisher version: http://dx.doi.org/10.3389/fimmu.2018.01009
Language: English
Additional information: © 2018 Easom, Stegmann, Swadling, Pallett, Burton, Odera, Schmidt, Huang, Fusai, Davidson and Maini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, NK cells, tissue-resident NK cells, hepatocellular carcinoma, liver tumors, NKG2D, tumor escape, immunotherapy, IL-15, NATURAL-KILLER-CELLS, HUMAN LIVER, T-CELLS, NKG2D RECEPTOR, CANCER-IMMUNOTHERAPY, HOST-DEFENSE, TUMOR-GROWTH, TISSUE, LIGANDS, SURVEILLANCE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10049710
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