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      The immune contexture of hepatocellular carcinoma predicts clinical outcome

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          Abstract

          The general relevance of the immune system for cancer development and therapy is increasingly recognized. However and although the immune contexture of most human cancer types has been determined, a global characterisation of the immune tumour microenvironment in hepatocellular carcinoma (HCC) is lacking. Equally, differences in the immune contexture of HCC between different patient subgroups and its effect on survival remain to be established. Here we report an in silico analysis of the immune contexture of human HCC. Using large deep sequencing HCC tumour, adjacent non-tumour and healthy liver high-dimensional data sets, we were able to reveal previously unrecognized differences in the immune contexture of HCC. Strikingly, we found that different etiologies and HCC stages were not associated with major changes in the immune contexture. In contrast, the presence of T cells and cytotoxic cells as well as the absence of macrophages and Th2 cells positively correlated with patient survival. Based on these novel findings, we developed a prognostic score that accurately distinguishes between patients with good and poor survival. Our study provides the first global characterisation of the immune contexture of HCC and will have direct implications for future HCC therapies.

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          Most cited references14

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          Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.

          Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease.
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            Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

            There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation.
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              Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment.

              Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.
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                Author and article information

                Contributors
                bockamp@uni-mainz.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                29 March 2018
                29 March 2018
                2018
                : 8
                : 5351
                Affiliations
                [1 ]ISNI 0000 0001 1941 7111, GRID grid.5802.f, Institute of Translational Immunology and Research Centre for Immunotherapy, University Medical Centre of the Johannes Gutenberg University Mainz, ; Mainz, Germany
                [2 ]GRID grid.410607.4, First Department of Medicine, , University Medical Centre of the Johannes Gutenberg University Mainz, ; Mainz, Germany
                [3 ]ISNI 0000 0001 1941 7111, GRID grid.5802.f, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Centre of the Johannes Gutenberg University Mainz, ; Mainz, Germany
                [4 ]Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
                Author information
                http://orcid.org/0000-0002-3234-8891
                Article
                21937
                10.1038/s41598-018-21937-2
                5876395
                29599491
                ba0e628b-c8d8-4b76-9d2b-cc66494843c5
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 September 2017
                : 13 February 2018
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