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Feun et al.                                                                                                                                                               Immunotherapy for hepatocellular carcinoma

           the blocking of TGF-β signaling in T-cells or deletion   Schemmer P, Bruns H, Eiermann T, Price DA, Blum HE, Neumann-
           of TGF-β from T-cells resulted in decreased PD-1      Haefelin C, Thimme R. Immunodominance and functional alterations
           expression in tumor-infiltrating CD8+ T-cells. [56]  Further   of tumor-associated antigen-specific CD8+ T-cell responses in
           studies in mice model of HCC showed that TGF-β     5.   hepatocellular carcinoma. Hepatology 2014;59:1415-26.
                                                                 Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF,
           increased the PD-L1 expression in dendritic cells     Korangy F. Increased populations of regulatory T cells in peripheral
           which led to T-cell apoptosis and increased number    blood of patients with hepatocellular carcinoma. Cancer Res
           of CD25+, Foxp3+ T regulatory cells.  [56,57]  Thus,   2005;65:2457-64.
           there is a strong rationale to target two pathways of   6.   Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW,
           immunosuppression in HCC simultaneously.              Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is
                                                                 associated with prognosis of hepatocellular carcinoma after resection.
           In summary, immunotherapy represents a novel       7.   J Clin Oncol 2007;25:2586-93.
                                                                 Zerbini A, Pilli M, Penna A, Pelosi G, Schianchi C, Molinari
           approach to treat advanced hepatocellular carcinoma.   A, Schivazappa S, Zibera C, Fagnoni FF, Ferrari C, Missale G.
           Immune cells have been found in HCC specimens         Radiofrequency thermal ablation of hepatocellular carcinoma liver
           that appear “fatigued” or suppressed. New checkpoint   nodules can activate and enhance tumor-specific T-cell responses.
           inhibitors  and  other  agents  may  awaken  these    Cancer Res 2006;66:1139-46.
           immune  cells  to  attack  the  tumor.  Early  results   8.   Wissniowski TT, Hänsler J, Neureiter D, Frieser M, Schaber S,
           from clinical trials suggest it is feasible to do so   Esslinger B, Voll R, Strobel D, Hahn EG, Schuppan D. Activation of
           and encouraging antitumor responses were been         tumor-specific T lymphocytes by radiofrequency ablation of the VX2
                                                                 hepatoma in rabbits. Cancer Res 2003;63:6496-500.
           observed. The challenge is to further define what   9.   Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T,
           patients may benefit from this approach, how to       Nakamoto Y, Kaneko S. Increase in CD14+HLA-DR -/low myeloid-
           predict or reduce toxicities, particularly liver toxicity,   derived suppressor cells in hepatocellular carcinoma patients and its
           and how best to combine this therapy with other       impact on prognosis. Cancer Immunol Immunother 2013;62:1421-
           known modalities of treatment.                        30.
                                                              10.  Ilkovitch D, Lopez DM. The liver is a site for tumor-induced
           Authors’ contributions                                myeloid-derived suppressor cell accumulation and immuno-
                                                                 suppression. Cancer Res 2009;69:5514-21.
           Manuscript writing and editing: L.G. Feun          11.  Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns
           Manuscript  review,  participating  in  the  phase  II   MP, Greten TF, Korangy F. A new population of myeloid-derived
           trial of Pembrolizumab in HCC, and performing the     suppressor cells in hepatocellular carcinoma patients induces CD4(+)
                                                                 CD25(+)Foxp3(+) T cells. Gastroenterology 2008;135:234-43.
           laboratory correlates: Y.Y. Li, M. Wangpaichitr, C.J.   12.  Greten TF, Ormandy LA, Fikuart A, Hochst B, Henschen S, Horning
           Wu, N. Savaraj                                        M, Manns MP, Korangy F. Low-dose cyclophosphamide treatment
                                                                 impairs regulatory T cells and unmasks AFP-specific CD4+
           Financial support and sponsorship                     T-cell responses in patients with advanced HCC. J Immunother
           None.                                                 2010;33:211-8.
                                                              13.  Han Y, Chen Z, Yang Y, Jiang Z, Gu Y, Liu Y, Lin C, Pan Z, Yu
           Conflicts of interest                                 Y, Jiang M, Zhou W, Cao X. Human CD14+CTLA4+ regulatory
                                                                 dendritic cells suppress T-cell response by cytotoxic T-lymphocyte
           There are no conflicts of interest.                   antigen-4-dependent IL-10 and indoleamine-2-3-dioxgenase
                                                                 production in hepatocellular carcinoma. Hepatology 2014;59:567-79.
           Patient consent                                    14.  Han Y, Yang Y, Chen Z, Jiang Z, Gu Y, Liu Y, Xu S, Lin C, Pan
                                                                 Z, Zhou W, Cao X. Human hepatocellular carcinoma-infiltrating
           There is no patient involved.                         CD4 CD69 Foxp3  regulatory T cell suppresses T cell response via
                                                                    +
                                                                             -
                                                                         +
                                                                 membrane-bound TGF-β1. J Mol Med (Berl) 2014;92:539-50.
           Ethics approval                                    15.  Kurokohchi K, Carrington M, Mann DL, Simonis TB, Alexander-
           This review paper is waived for ethics approval.      Miller MA, Feinstone SM, Akatsuka T, Berzofsky JA. Expression
                                                                 of HLA class I molecules and the transporter associated with antigen
                                                                 processing in hepatocellular carcinoma. Hepatology 1996;23:1181-8.
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