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      Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma

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          Abstract

          The tumor microenvironment generally shows a substantial immunosuppressive activity in hepatocellular carcinoma (HCC), accounting for the suboptimal efficacy of immune-based treatments for this difficult-to-treat cancer. The crosstalk between tumor cells and various cell types in the tumor microenvironment is strongly related to HCC progression and treatment resistance. Monocytes are recruited to the HCC tumor microenvironment by various factors and become tumor-associated macrophages (TAMs) with distinct phenotypes. TAMs often contribute to weakened tumor-specific immune responses and a more aggressive phenotype of malignancy. Recent single-cell RNA-sequencing data have demonstrated the central roles of specific TAMs in tumorigenesis and treatment resistance by their interactions with various cell populations in the HCC tumor microenvironment. This review focuses on the roles of TAMs and the crosstalk between TAMs and neighboring cell types in the HCC tumor microenvironment.

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          Most cited references149

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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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            The Immune Landscape of Cancer

            We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
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              Hepatocellular carcinoma

              Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.
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                Author and article information

                Journal
                Clin Mol Hepatol
                Clin Mol Hepatol
                CMH
                Clinical and Molecular Hepatology
                The Korean Association for the Study of the Liver
                2287-2728
                2287-285X
                July 2022
                19 October 2021
                : 28
                : 3
                : 333-350
                Affiliations
                [1 ]The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
                [2 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
                Author notes
                Corresponding author : Pil Soo Sung Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2258-2073, Fax: +82-2-3481-4025 E-mail: pssung@ 123456catholic.ac.kr

                Editor: Naoshi Nishida, Kindai University, Japan

                Author information
                http://orcid.org/0000-0002-5780-9607
                Article
                cmh-2021-0308
                10.3350/cmh.2021.0308
                9293612
                34665953
                a389eb84-a096-4429-8128-91ccf86ec31b
                Copyright © 2022 by The Korean Association for the Study of the Liver

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 September 2021
                : 16 October 2021
                : 18 October 2021
                Categories
                Review

                Gastroenterology & Hepatology
                carcinoma, hepatocellular,immunotherapy,tumor-associated macrophages,tumor microenvironment

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