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      A classification based on tumor budding and immune score for patients with hepatocellular carcinoma

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          ABSTRACT

          Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score.

          Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing.

          Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma ( P < .001), strong α-SMA expression ( P = .005), non-steatotic tumors and non-fibrolamellar-HCC ( P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: IS A-TB high (type I), IS B-TB high (type II), IS A-TB low (type III) and IS B-TB low (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (IS ATB high) patients, while IS-TB type IV (IS BTB low) harbored high number of CTNNB1 mutation.

          Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.

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          Most cited references36

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          Histological Subtypes of Hepatocellular Carcinoma Are Related To Gene Mutations and Molecular Tumour Classification.

          Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype.
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            Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma

            Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50–60% of the patients have no clinical benefit. Here, we searched for predictive biomarkers to ACT in melanoma. Whole exome- and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously progressed on other immunotherapies. We report that clinical benefit is associated with significantly higher predicted neoantigen load. High mutation and predicted neoantigen load are significantly associated with improved progression-free and overall survival. Further, clinical benefit is associated with the expression of immune activation signatures including a high MHC-I antigen processing and presentation score. These results improve our understanding of mechanisms behind clinical benefit of ACT in melanoma.
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              Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma

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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                KONI
                koni20
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                2020
                7 November 2019
                7 November 2019
                : 9
                : 1
                : 1672495
                Affiliations
                [a ]Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy , Chengdu, China
                [b ]Department of Plastic and Burns Surgery, West China Hospital, Sichuan University , Chengdu, China
                Author notes
                CONTACT Zhang Yange 58131972@ 123456qq.com Department of Plastic and Burns Surgery, West China Hospital, Sichuan University , Chengdu 610041, China
                [*]

                Co-first author.

                Article
                1672495
                10.1080/2162402X.2019.1672495
                6959452
                32002283
                28490fd8-c494-4fac-88a7-6aa02559222a
                © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 May 2019
                : 18 September 2019
                : 21 September 2019
                Page count
                Figures: 6, Tables: 2, References: 51, Pages: 13
                Funding
                Funded by: Project of science and Technology Department of Sichuan Province
                Award ID: 2017FZ0048
                This work was supported by grants from the National Key Technologies R&D Program [2018YFC1106800]; the Natural Science Foundation of China [81872004, 81800564, 81770615, 81700555 and 81672882]; the Science and Technology Support Program of Sichuan Province [2017SZ0003, 2018SZ0115 and 2017FZ0048]; the Science and Technology Program of Tibet Autonomous Region [XZ201801-GB-02] and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYJC18008].
                Categories
                Original Research

                Immunology
                hepatocellular carcinoma,tumor budding,immune score,prognosis,whole exome sequencing
                Immunology
                hepatocellular carcinoma, tumor budding, immune score, prognosis, whole exome sequencing

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