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      On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C

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          Abstract

          Background and aims

          Interferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs.

          Methods

          We conducted a clinical practice-based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN-combined protease inhibitor.

          Results

          We found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92).

          Conclusions

          On-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs.

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          Most cited references32

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          EASL Recommendations on Treatment of Hepatitis C 2015.

          (2015)
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            Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity.

            NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-β1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity.
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              Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts.

              (2016)
              Sustained virological response following interferon-based antiviral treatment of chronic hepatitis C is associated with decreased long-term risk of hepatocellular carcinoma (HCC) in advanced liver fibrosis. An unexpected high rate of HCC recurrence following antiviral treatment using direct-acting antiviral (DAA) has recently been reported.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Writing – original draft
                Role: Conceptualization
                Role: Investigation
                Role: Conceptualization
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Conceptualization
                Role: Conceptualization
                Role: ConceptualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 June 2017
                2017
                : 12
                : 6
                : e0179096
                Affiliations
                [1 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
                [2 ]Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
                [3 ]Kitasato University Kitasato Institute Hospital, 5-9-1 Shiragane-dai, Minato-ku, Tokyo, Japan
                [4 ]Eiju Hospital, 2-23-16 Higashi-ueno, Ueno-ku, Tokyo, Japan
                [5 ]International University of Health and Welfare Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, Japan
                [6 ]Division of Pharmacotherapeutics, Keio University School of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan
                National Taiwan University Hospital, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-8687-2760
                Article
                PONE-D-17-07307
                10.1371/journal.pone.0179096
                5472371
                28617830
                0235b5ef-a188-4a57-98ee-efebaacb31ca
                © 2017 Chu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 February 2017
                : 23 May 2017
                Page count
                Figures: 6, Tables: 4, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 15fk0210037h0101
                Funded by: Keio Gijuku Academic Development Funds
                This study was supported in part by grants-in-aid from the Keio Gijuku Academic Development Funds and Japan Agency for Medical Research and Development (grant number: 15fk0210037h0101). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Oncology
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                Hepatocellular Carcinoma
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