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      Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy

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          Abstract

          Hepatocellular carcinoma (HCC) remains a serious medical therapeutic challenge as conventional curative avenues such as surgery and chemotherapy only benefit for few patients with limited tumor burden. Immunotherapy achieves clinical progress in the treatment of this prevalent malignant disease by virtue of the development of tumor immunology; however, most patients have experienced minimal or no clinical benefit in terms of overall survival. The complexity and diversity of tumor microenvironment (TME) built by immune and stromal cell subsets has been considered to be responsible for the insufficiency of immunotherapy. The advance of bioanalytical technology boosts the exploration of the composition and differentiation of these infiltrated cells, which reflect the immune state of the TME and impact the efficacy of the antitumor immune response. Targeting these cells to remodel the TME is one of the important immunotherapeutic approaches to improve HCC treatment. In this review, we focused on the role of these non-cancerous cells in the tumor progression, and elaborated their function on cancer immunotherapy when manipulating them as potential targets.

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          Most cited references147

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          Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

          The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
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            Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

            An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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              Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

              Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006). Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).
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                Author and article information

                Journal
                J Hepatocell Carcinoma
                J Hepatocell Carcinoma
                jhc
                Journal of Hepatocellular Carcinoma
                Dove
                2253-5969
                26 October 2022
                2022
                : 9
                : 1109-1125
                Affiliations
                [1 ]Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China
                [2 ]Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China
                [3 ]Department of Informatics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China
                Author notes
                Correspondence: Yueqiu Gao, Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email gaoyueqiu@shutcm.edu.cn
                Zhuo Yu, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email zhuoyu@shutcm.edu.cn
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0001-9820-7111
                http://orcid.org/0000-0003-0846-3299
                http://orcid.org/0000-0003-4100-8415
                Article
                381764
                10.2147/JHC.S381764
                9618253
                36320666
                5fd5a3d7-1b00-4e18-b736-b3f226abcd05
                © 2022 Feng et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 14 July 2022
                : 19 October 2022
                Page count
                Figures: 3, Tables: 1, References: 147, Pages: 17
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: The Siming Scholar from Shanghai Shuguang Hospital;
                Funded by: Youth Tip-top Talent program in Shanghai, Constant-eminent program in Shanghai, Xinglin Youth Scholar from Shanghai University of Traditional Chinese Medicine, Three-year Action Plan for the Development of Chinese Medicine in Shanghai;
                Funded by: Shanghai Key Clinical Specialty Construction Project;
                Funded by: Shanghai Key Laboratory of Traditional Chinese Clinical Medicine;
                Funded by: Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education;
                This work was supported by National Natural Science Foundation of China (No. 82222074, 82074154, 81774240), The Siming Scholar from Shanghai Shuguang Hospital (SGXZ-201904), Youth Tip-top Talent program in Shanghai, Constant-eminent program in Shanghai, Xinglin Youth Scholar from Shanghai University of Traditional Chinese Medicine, Three-year Action Plan for the Development of Chinese Medicine in Shanghai (No.ZY (2018-2020)-CCCX-2003-01), Shanghai Key Clinical Specialty Construction Project (No.shslczdzk01201), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (20DZ2272200), Key Laboratory of Liver and Kidney Diseases (Shanghai University of Traditional Chinese Medicine), Ministry of Education.
                Categories
                Review

                immune cells,stromal cells,tumor microenvironment,hepatocellular carcinoma,immunotherapy

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