N Jannah M Nasir, Samuel Chuah, Timothy Shuen, Aldo Prawira, Rebecca Ba, Mei Chee Lim, Joelle Chua, Phuong H D Nguyen, Chun J Lim, Martin Wasser, Sharifah N Hazirah, Tony K H Lim, Wei Qiang Leow, Tracy Jiezhen Loh, Wei Keat Wan, Yin Huei Pang, Gwyneth Soon, Peng Chung Cheow, Juinn Huar Kam, Shridhar Iyer, Alfred Kow, Yock Young Dan, Glenn K Bonney, Alexander Chung, Brian K P Goh, Pierce K H Chow, Salvatore Albani, Weiwei Zhai, John F Ouyang, Han Chong Toh, Valerie Chew
{"title":"GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma.","authors":"N Jannah M Nasir, Samuel Chuah, Timothy Shuen, Aldo Prawira, Rebecca Ba, Mei Chee Lim, Joelle Chua, Phuong H D Nguyen, Chun J Lim, Martin Wasser, Sharifah N Hazirah, Tony K H Lim, Wei Qiang Leow, Tracy Jiezhen Loh, Wei Keat Wan, Yin Huei Pang, Gwyneth Soon, Peng Chung Cheow, Juinn Huar Kam, Shridhar Iyer, Alfred Kow, Yock Young Dan, Glenn K Bonney, Alexander Chung, Brian K P Goh, Pierce K H Chow, Salvatore Albani, Weiwei Zhai, John F Ouyang, Han Chong Toh, Valerie Chew","doi":"10.1097/HC9.0000000000000508","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 9","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340929/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatology Communications","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/HC9.0000000000000508","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction.
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