1. GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma.
- Author
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Nasir NJM, Chuah S, Shuen T, Prawira A, Ba R, Lim MC, Chua J, Nguyen PHD, Lim CJ, Wasser M, Hazirah SN, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Dan YY, Bonney GK, Chung A, Goh BKP, Chow PKH, Albani S, Zhai W, Ouyang JF, Toh HC, and Chew V
- Subjects
- Humans, Gene Expression Regulation, Neoplastic, Immune Tolerance, Myeloid-Derived Suppressor Cells immunology, Male, T-Lymphocytes, Regulatory immunology, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular mortality, Liver Neoplasms immunology, Liver Neoplasms genetics, Liver Neoplasms mortality, Liver Neoplasms pathology, GATA4 Transcription Factor genetics, Chemokine CCL20 genetics, Down-Regulation, Tumor Microenvironment immunology
- Abstract
Background: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC., Methods: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence., Results: GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression., Conclusions: Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
- Published
- 2024
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