{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:00:00Z","timestamp":1790676000633,"version":"4.1.0"},"reference-count":103,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T00:00:00Z","timestamp":1634256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor \u2264 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.<\/jats:p>","DOI":"10.3390\/vaccines9101184","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:25:15Z","timestamp":1634513115000},"page":"1184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["The Immunology of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"9","author":[{"given":"Gbemisola","family":"Lawal","sequence":"first","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-9813","authenticated-orcid":false,"given":"Yao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir A.","family":"Rahnemai-Azar","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diamantis I.","family":"Tsilimigras","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anargyros","family":"Bakopoulos","sequence":"additional","affiliation":[{"name":"Department of Surgery, Attikon University Hospital, University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"ref_1","unstructured":"Townsend, C.M., Beauchamp, R.D., Mattox, K.L., and Evers, B.M. (2017). Sabiston Textbook of Surgery, Elsevier Saunders."},{"key":"ref_2","unstructured":"Brunicardi, F.C., Andersen, D.K., Billiar, T.R., Dunn, D.L., Hunter, J.G., Kao, L., Matthews, J.B., and Pollock, R.E. (2019). Chapter 1: Leadership in Surgery. Schwartz Principles of Surgery, Available online: https:\/\/accessmedicine.mhmedical.com\/content.aspx?bookid=2576&sectionid=210404908."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41575-019-0186-y","article-title":"A global view of hepatocellular carcinoma: Trends, risk, prevention and management","volume":"16","author":"Yang","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jhep.2016.09.008","article-title":"The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma","volume":"66","author":"Pinato","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s12072-018-9919-1","article-title":"Goals and targets for personalized therapy for HCC","volume":"13","author":"Couri","year":"2019","journal-title":"Hepatol. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1159\/000488916","article-title":"Immunotherapy of Hepatocellular Carcinoma","volume":"41","author":"Heinrich","year":"2018","journal-title":"Oncol. Res. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Abd El Aziz, M.A., Facciorusso, A., Nayfeh, T., Saadi, S., Elnaggar, M., Cotsoglou, C., and Sacco, R. (2020). Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma. Vaccines, 8.","DOI":"10.3390\/vaccines8040616"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1056\/NEJMoa0708857","article-title":"Sorafenib in advanced hepatocellular carcinoma","volume":"359","author":"Llovet","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1158\/1535-7163.MCT-08-0013","article-title":"Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling","volume":"7","author":"Wilhelm","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tovoli, F., De Lorenzo, S., and Trevisani, F. (2020). Immunotherapy with Checkpoint Inhibitors for Hepatocellular Carcinoma: Where Are We Now?. Vaccines, 8.","DOI":"10.3390\/vaccines8040578"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tahmasebi Birgani, M., and Carloni, V. (2017). Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020405"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41419-020-2509-x","article-title":"Oncogenic driver genes and tumor microenvironment determine the type of liver cancer","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1186\/s13046-019-1396-4","article-title":"From bench to bed: The tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma","volume":"38","author":"Fu","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Patel, K., Lamm, R., Altshuler, P., Dang, H., and Shah, A.P. (2020). Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186757"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1186\/s40425-019-0749-z","article-title":"Immunotherapy in hepatocellular carcinoma: The complex interface between inflammation, fibrosis, and the immune response","volume":"7","author":"Keenan","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1053\/j.gastro.2014.08.039","article-title":"Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells","volume":"147","author":"Wan","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9419","DOI":"10.1002\/jcb.27259","article-title":"IL-6\/STAT3 pathway intermediates M1\/M2 macrophage polarization during the development of hepatocellular carcinoma","volume":"119","author":"Yin","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12957-018-1312-y","article-title":"M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4\/STAT3 signaling pathway","volume":"16","author":"Yao","year":"2018","journal-title":"World J. Surg. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.3389\/fonc.2019.01146","article-title":"Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy","volume":"9","author":"Masucci","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6862439","DOI":"10.1155\/2017\/6862439","article-title":"Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease","volume":"2017","author":"Byun","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s13046-015-0256-0","article-title":"Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1\/PD-1 signalling pathway in hepatocellular carcinoma","volume":"34","author":"He","year":"2015","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.4049\/jimmunol.0903275","article-title":"Tim-3\/galectin-9 pathway: Regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells","volume":"185","author":"Dardalhon","year":"2010","journal-title":"J. Immunol. (Baltimore Md. 1950)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1053\/j.gastro.2008.03.020","article-title":"A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells","volume":"135","author":"Hoechst","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15129","DOI":"10.1038\/ncomms15129","article-title":"The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion","volume":"8","author":"Jiang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Park, R., Eshrat, F., Al-Jumayli, M., Saeed, A., and Saeed, A. (2020). Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma. Vaccines, 8.","DOI":"10.3390\/vaccines8030447"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/hep.29844","article-title":"Identification of \u03b1-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy","volume":"68","author":"Zhu","year":"2018","journal-title":"Hepatology (Baltim Md.)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.3892\/ijo.2012.1626","article-title":"Phase I\/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma","volume":"41","author":"Tada","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.jhep.2017.05.019","article-title":"Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models","volume":"67","author":"Lu","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1346764","DOI":"10.1080\/2162402X.2017.1346764","article-title":"Immunological efficacy of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma","volume":"6","author":"Tsuchiya","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13046-018-0777-4","article-title":"Immune checkpoint therapy in liver cancer","volume":"37","author":"Xu","year":"2018","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nri.2017.108","article-title":"The diverse functions of the PD1 inhibitory pathway","volume":"18","author":"Sharpe","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.jhep.2019.05.015","article-title":"TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma","volume":"71","author":"Wang","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1159\/000490025","article-title":"Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy","volume":"47","author":"Zhao","year":"2018","journal-title":"Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00262-019-02299-8","article-title":"The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma","volume":"68","author":"Agdashian","year":"2019","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"584423","DOI":"10.3389\/fimmu.2020.584423","article-title":"Tumor Infiltrating Effector Memory Antigen-Specific CD8(+) T Cells Predict Response to Immune Checkpoint Therapy","volume":"11","author":"Principe","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8740976","DOI":"10.1155\/2018\/8740976","article-title":"Immunotherapy for Hepatocellular Carcinoma: Current Advances and Future Expectations","volume":"2018","author":"Xie","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1126\/science.aar6711","article-title":"CAR T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science (N. Y.)"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.3389\/fphar.2018.01118","article-title":"Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma","volume":"9","author":"Guo","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1053\/j.gastro.2020.02.011","article-title":"Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice","volume":"158","author":"Li","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1158\/2326-6066.CIR-19-0026","article-title":"Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells","volume":"7","author":"Sun","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_41","first-page":"156","article-title":"Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy","volume":"13","author":"Li","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00262-016-1949-8","article-title":"Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma","volume":"66","author":"Chen","year":"2017","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1158\/1078-0432.CCR-16-1203","article-title":"Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer","volume":"23","author":"Liu","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1016\/j.ymthe.2021.01.021","article-title":"The CD39(+) HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8(+) T cells exhibit potent anti-HCC activity","volume":"29","author":"Zou","year":"2021","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3389\/fcell.2019.00233","article-title":"Doxycycline Inducible Chimeric Antigen Receptor T Cells Targeting CD147 for Hepatocellular Carcinoma Therapy","volume":"7","author":"Zhang","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4810","DOI":"10.1038\/s41467-020-18444-2","article-title":"Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma","volume":"11","author":"Tseng","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1158\/1078-0432.CCR-19-3259","article-title":"Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials","volume":"26","author":"Shi","year":"2020","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/21645515.2017.1285987","article-title":"Cell-based immunotherapy with cytokine-induced killer (CIK) cells: From preparation and testing to clinical application","volume":"13","author":"Meng","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3748\/wjg.v8.i3.464","article-title":"Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo","volume":"8","author":"Wang","year":"2002","journal-title":"World J. Gastroenterol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.3748\/wjg.v11.i22.3339","article-title":"CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402\/R","volume":"11","author":"Zhang","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1086060","DOI":"10.1080\/2162402X.2015.1086060","article-title":"Recognition and killing of cancer stem-like cell population in hepatocellular carcinoma cells by cytokine-induced killer cells via NKG2d-ligands recognition","volume":"5","author":"Rong","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Yang, T., Zhang, W., Wang, L., Xiao, C., Wang, L., Gong, Y., Huang, D., Guo, B., Li, Q., and Xiang, Y. (2018). Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4871-y"},{"key":"ref_53","first-page":"369","article-title":"Patient-derived dendritic cells transduced with an a-fetoprotein-encoding adenovirus and co-cultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against hepatocellular carcinoma cells","volume":"26","author":"Hoffmann","year":"2006","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"581270","DOI":"10.3389\/fonc.2020.581270","article-title":"One Single Site Clinical Study: To Evaluate the Safety and Efficacy of Immunotherapy With Autologous Dendritic Cells, Cytokine-Induced Killer Cells in Primary Hepatocellular Carcinoma Patients","volume":"10","author":"Xu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.3748\/wjg.v25.i27.3649","article-title":"Immunotherapy with dendritic cells and cytokine-induced killer cells for hepatocellular carcinoma: A meta-analysis","volume":"25","author":"Cao","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_56","first-page":"1449","article-title":"High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients","volume":"38","author":"Chang","year":"2018","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00262-020-02486-y","article-title":"CIK cell cytotoxicity is a predictive biomarker for CIK cell immunotherapy in postoperative patients with hepatocellular carcinoma","volume":"69","author":"Pan","year":"2020","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"596","DOI":"10.5732\/cjc.009.10580","article-title":"Serum alpha-fetoprotein measurement in predicting clinical outcome related to autologous cytokine-induced killer cells in patients with hepatocellular carcinoma undergone minimally invasive therapy","volume":"29","author":"Pan","year":"2010","journal-title":"Chin. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e001748","DOI":"10.1136\/jitc-2020-001748","article-title":"In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma","volume":"8","author":"Liu","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1002\/hep.30477","article-title":"Tuning T-Cell Receptor Affinity to Optimize Clinical Risk-Benefit When Targeting Alpha-Fetoprotein-Positive Liver Cancer","volume":"69","author":"Docta","year":"2019","journal-title":"Hepatology (Baltim. Md.)"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Goyal, L., Frigault, M., Meyer, T., Feun, L.G., Bruix, J., El-Khoueiry, A., Hausner, P., Sangro, B., Pierce, T.T., and Norry, E. (2019). Initial safety of AFP SPEAR T-cells in patients with advanced hepatocellular carcinoma. AACR, 79.","DOI":"10.1158\/1538-7445.SABCS18-3183"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3389\/fimmu.2020.00623","article-title":"Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit","volume":"11","author":"Luo","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2009.07.013","article-title":"Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients","volume":"52","author":"Chew","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1053\/j.gastro.2017.06.017","article-title":"Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas","volume":"153","author":"Zhou","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"41339","DOI":"10.18632\/oncotarget.5463","article-title":"A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma","volume":"6","author":"Jiang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1146\/annurev-pharmtox-010814-124844","article-title":"Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy","volume":"56","author":"Gross","year":"2016","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1158\/2159-8290.CD-16-0040","article-title":"Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia","volume":"6","author":"Teachey","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.canlet.2013.10.004","article-title":"Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells","volume":"343","author":"Xu","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1001\/jama.2014.7189","article-title":"Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: The EVOLVE-1 randomized clinical trial","volume":"312","author":"Zhu","year":"2014","journal-title":"JAMA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e000932","DOI":"10.1136\/jitc-2020-000932","article-title":"Integrated immunological analysis of a successful conversion of locally advanced hepatocellular carcinoma to resectability with neoadjuvant therapy","volume":"8","author":"Ho","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e204564","DOI":"10.1001\/jamaoncol.2020.4564","article-title":"Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial","volume":"6","author":"Yau","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1200\/JCO.2020.38.4_suppl.512","article-title":"Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Subgroup analyses from CheckMate 040","volume":"38","author":"He","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1200\/JCO.2017.35.15_suppl.4073","article-title":"Phase I\/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses","volume":"35","author":"Kelley","year":"2017","journal-title":"Am. Soc. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1038\/s41388-020-1249-9","article-title":"Immune-based therapies for hepatocellular carcinoma","volume":"39","author":"Pinato","year":"2020","journal-title":"Oncogene"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"17675","DOI":"10.18632\/oncotarget.24832","article-title":"A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies","volume":"9","author":"Vey","year":"2018","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.cell.2018.10.014","article-title":"Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells","volume":"175","author":"Denis","year":"2018","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1053\/j.gastro.2017.05.045","article-title":"Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1","volume":"153","author":"Jin","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41392-020-0187-x","article-title":"The mechanisms of sorafenib resistance in hepatocellular carcinoma: Theoretical basis and therapeutic aspects","volume":"5","author":"Tang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"v874","DOI":"10.1093\/annonc\/mdz394.029","article-title":"CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)","volume":"30","author":"Yau","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Llovet, J.M., Kudo, M., Cheng, A.-L., Finn, R.S., Galle, P.R., Kaneko, S., Meyer, T., Qin, S., Dutcus, C.E., and Chen, E. (2019). Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study. Am. Soc. Clin. Oncol., 37.","DOI":"10.1200\/JCO.2019.37.15_suppl.TPS4152"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Kudo, M., Motomura, K., Wada, Y., Inaba, Y., Sakamoto, Y., Kurosaki, M., Umeyama, Y., Kamei, Y., Yoshimitsu, J., and Fujii, Y. (2019). First-line avelumab+ axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100). Am. Soc. Clin. Oncol., 37.","DOI":"10.1200\/JCO.2019.37.15_suppl.4072"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.jhep.2019.01.027","article-title":"Combined locoregional-immunotherapy for liver cancer","volume":"70","author":"Greten","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jhep.2016.10.029","article-title":"Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma","volume":"66","author":"Duffy","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"v288","DOI":"10.1093\/annonc\/mdz247.076","article-title":"A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL","volume":"30","author":"Pinato","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.canlet.2017.04.013","article-title":"Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies","volume":"399","author":"Hoseini","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"eaal4291","DOI":"10.1126\/scitranslmed.aal4291","article-title":"An anti-glypican 3\/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors","volume":"9","author":"Ishiguro","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1\/2 dose escalation and expansion trial","volume":"389","author":"Sangro","year":"2017","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00262-018-2271-4","article-title":"The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma","volume":"68","author":"Chang","year":"2019","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e000394","DOI":"10.1136\/jitc-2019-000394","article-title":"Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma","volume":"8","author":"Ho","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor Mutational Burden and Response Rate to PD-1 Inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.18632\/oncotarget.26998","article-title":"Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma","volume":"10","author":"Ang","year":"2019","journal-title":"Oncotarget"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/hepr.13496","article-title":"Incidence of microsatellite instability-high hepatocellular carcinoma among Japanese patients and response to pembrolizumab","volume":"50","author":"Kawaoka","year":"2020","journal-title":"Hepatol. Res. Off. J. Jpn. Soc. Hepatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1158\/1078-0432.CCR-15-1678","article-title":"Microsatellite Instability as a Biomarker for PD-1 Blockade","volume":"22","author":"Dudley","year":"2016","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science (N. Y.)"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1158\/1078-0432.CCR-18-2293","article-title":"Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next-Generation Sequencing for Matching Patients to Targeted and Immune Therapies","volume":"25","author":"Harding","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12943-020-01222-5","article-title":"Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"eabc4552","DOI":"10.1126\/science.abc4552","article-title":"The microbiome and human cancer","volume":"371","author":"Zitvogel","year":"2021","journal-title":"Science (N. Y.)"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s40425-019-0650-9","article-title":"Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma","volume":"7","author":"Zheng","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1002\/cncr.32339","article-title":"Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma","volume":"125","author":"Feun","year":"2019","journal-title":"Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s40425-019-0766-y","article-title":"Immunotherapy response evaluation with magnetic resonance elastography (MRE) in advanced HCC","volume":"7","author":"Qayyum","year":"2019","journal-title":"J. Immunother. Cancer"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/10\/1184\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:15:11Z","timestamp":1760166911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/10\/1184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,15]]},"references-count":103,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["vaccines9101184"],"URL":"https:\/\/doi.org\/10.3390\/vaccines9101184","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,15]]}}}