GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma
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. HCC tumor samples were classi...
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| creator | Nasir, N Jannah M Chuah, Samuel Shuen, Timothy Prawira, Aldo Ba, Rebecca Lim, Mei Chee Chua, Joelle Nguyen, Phuong H D Lim, Chun J Wasser, Martin Hazirah, Sharifah N Lim, Tony K H Leow, Wei Qiang Loh, Tracy Jiezhen Wan, Wei Keat Pang, Yin Huei Soon, Gwyneth Cheow, Peng Chung Kam, Juinn Huar Iyer, Shridhar Kow, Alfred Dan, Yock Young Bonney, Glenn K Chung, Alexander Goh, Brian K P Chow, Pierce K H Albani, Salvatore Zhai, Weiwei Ouyang, John F Toh, Han Chong Chew, Valerie |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1097/HC9.0000000000000508 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 2471-254X</identifier><identifier>EISSN: 2471-254X</identifier><identifier>DOI: 10.1097/HC9.0000000000000508</identifier><identifier>PMID: 39167427</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins</publisher><subject>Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - immunology ; Carcinoma, Hepatocellular - mortality ; Chemokine CCL20 - genetics ; Down-Regulation ; GATA4 Transcription Factor - genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Immune Tolerance ; Liver Neoplasms - genetics ; Liver Neoplasms - immunology ; Liver Neoplasms - mortality ; Liver Neoplasms - pathology ; Male ; Myeloid-Derived Suppressor Cells - immunology ; Original ; T-Lymphocytes, Regulatory - immunology ; Tumor Microenvironment - immunology</subject><ispartof>Hepatology communications, 2024-09, Vol.8 (9)</ispartof><rights>Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.</rights><rights>Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c288t-badb359a7539a155925a8e653e24bf7ae8f3e77a13ff3916fa3608ca142ce0703</cites><orcidid>0000-0002-5617-0936 ; 0000-0003-3700-9036 ; 0000-0001-9305-7652</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340929/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340929/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39167427$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nasir, N Jannah M</creatorcontrib><creatorcontrib>Chuah, Samuel</creatorcontrib><creatorcontrib>Shuen, Timothy</creatorcontrib><creatorcontrib>Prawira, Aldo</creatorcontrib><creatorcontrib>Ba, Rebecca</creatorcontrib><creatorcontrib>Lim, Mei Chee</creatorcontrib><creatorcontrib>Chua, Joelle</creatorcontrib><creatorcontrib>Nguyen, Phuong H D</creatorcontrib><creatorcontrib>Lim, Chun J</creatorcontrib><creatorcontrib>Wasser, Martin</creatorcontrib><creatorcontrib>Hazirah, Sharifah N</creatorcontrib><creatorcontrib>Lim, Tony K H</creatorcontrib><creatorcontrib>Leow, Wei Qiang</creatorcontrib><creatorcontrib>Loh, Tracy Jiezhen</creatorcontrib><creatorcontrib>Wan, Wei Keat</creatorcontrib><creatorcontrib>Pang, Yin Huei</creatorcontrib><creatorcontrib>Soon, Gwyneth</creatorcontrib><creatorcontrib>Cheow, Peng Chung</creatorcontrib><creatorcontrib>Kam, Juinn Huar</creatorcontrib><creatorcontrib>Iyer, Shridhar</creatorcontrib><creatorcontrib>Kow, Alfred</creatorcontrib><creatorcontrib>Dan, Yock Young</creatorcontrib><creatorcontrib>Bonney, Glenn K</creatorcontrib><creatorcontrib>Chung, Alexander</creatorcontrib><creatorcontrib>Goh, Brian K P</creatorcontrib><creatorcontrib>Chow, Pierce K H</creatorcontrib><creatorcontrib>Albani, Salvatore</creatorcontrib><creatorcontrib>Zhai, Weiwei</creatorcontrib><creatorcontrib>Ouyang, John F</creatorcontrib><creatorcontrib>Toh, Han Chong</creatorcontrib><creatorcontrib>Chew, Valerie</creatorcontrib><title>GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma</title><title>Hepatology communications</title><addtitle>Hepatol Commun</addtitle><description>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.
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.
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.
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.</description><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - immunology</subject><subject>Carcinoma, Hepatocellular - mortality</subject><subject>Chemokine CCL20 - genetics</subject><subject>Down-Regulation</subject><subject>GATA4 Transcription Factor - genetics</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immune Tolerance</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - immunology</subject><subject>Liver Neoplasms - mortality</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Myeloid-Derived Suppressor Cells - immunology</subject><subject>Original</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Tumor Microenvironment - immunology</subject><issn>2471-254X</issn><issn>2471-254X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUU1LxDAQDaKoqP9ApEcv1Xw0m-YkS_ELFrysIF7CbHbqRtqkJq3iv7fLqqzOZQbmvTdveIScMnrBqFaXd5W-oNslablDDnmhWM5l8bS7NR-Qk5ReRwzTnDFN98mB0GyiCq4OyfPtdD4tsmX48BFfhgZ6F3yGfgXeYsqqasZp3uLSQY_LzLXt4EMaui5iSmuk89kKO-iDxaYZ6TGzEK3zoYVjsldDk_Dkux-Rx5vreXWXzx5u76vpLLe8LPt8AcuFkBqUFBqYlJpLKHEiBfJiUSvAshaoFDBR12vfNYgJLS2wglukioojcrXR7YbF6NSi7yM0pouuhfhpAjjzd-PdyryEd8OYKKjmelQ4_1aI4W3A1JvWpfVD4DEMyQiq5USJUrIRWmygNoaUIta_dxg162jMGI35H81IO9v2-Ev6CUJ8AXLBivQ</recordid><startdate>20240901</startdate><enddate>20240901</enddate><creator>Nasir, N Jannah M</creator><creator>Chuah, Samuel</creator><creator>Shuen, Timothy</creator><creator>Prawira, Aldo</creator><creator>Ba, Rebecca</creator><creator>Lim, Mei Chee</creator><creator>Chua, Joelle</creator><creator>Nguyen, Phuong H D</creator><creator>Lim, Chun J</creator><creator>Wasser, Martin</creator><creator>Hazirah, Sharifah N</creator><creator>Lim, Tony K H</creator><creator>Leow, Wei Qiang</creator><creator>Loh, Tracy Jiezhen</creator><creator>Wan, Wei Keat</creator><creator>Pang, Yin Huei</creator><creator>Soon, Gwyneth</creator><creator>Cheow, Peng Chung</creator><creator>Kam, Juinn Huar</creator><creator>Iyer, Shridhar</creator><creator>Kow, Alfred</creator><creator>Dan, Yock Young</creator><creator>Bonney, Glenn K</creator><creator>Chung, Alexander</creator><creator>Goh, Brian K P</creator><creator>Chow, Pierce K H</creator><creator>Albani, Salvatore</creator><creator>Zhai, Weiwei</creator><creator>Ouyang, John F</creator><creator>Toh, Han Chong</creator><creator>Chew, Valerie</creator><general>Lippincott Williams & Wilkins</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5617-0936</orcidid><orcidid>https://orcid.org/0000-0003-3700-9036</orcidid><orcidid>https://orcid.org/0000-0001-9305-7652</orcidid></search><sort><creationdate>20240901</creationdate><title>GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma</title><author>Nasir, N Jannah M ; Chuah, Samuel ; Shuen, Timothy ; Prawira, Aldo ; Ba, Rebecca ; Lim, Mei Chee ; Chua, Joelle ; Nguyen, Phuong H D ; Lim, Chun J ; Wasser, Martin ; Hazirah, Sharifah N ; Lim, Tony K H ; Leow, Wei Qiang ; Loh, Tracy Jiezhen ; Wan, Wei Keat ; Pang, Yin Huei ; Soon, Gwyneth ; Cheow, Peng Chung ; Kam, Juinn Huar ; Iyer, Shridhar ; Kow, Alfred ; Dan, Yock Young ; Bonney, Glenn K ; Chung, Alexander ; Goh, Brian K P ; Chow, Pierce K H ; Albani, Salvatore ; Zhai, Weiwei ; Ouyang, John F ; Toh, Han Chong ; Chew, Valerie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c288t-badb359a7539a155925a8e653e24bf7ae8f3e77a13ff3916fa3608ca142ce0703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - immunology</topic><topic>Carcinoma, Hepatocellular - mortality</topic><topic>Chemokine CCL20 - genetics</topic><topic>Down-Regulation</topic><topic>GATA4 Transcription Factor - genetics</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immune Tolerance</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - immunology</topic><topic>Liver Neoplasms - mortality</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Myeloid-Derived Suppressor Cells - immunology</topic><topic>Original</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Tumor Microenvironment - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nasir, N Jannah M</creatorcontrib><creatorcontrib>Chuah, Samuel</creatorcontrib><creatorcontrib>Shuen, Timothy</creatorcontrib><creatorcontrib>Prawira, Aldo</creatorcontrib><creatorcontrib>Ba, Rebecca</creatorcontrib><creatorcontrib>Lim, Mei Chee</creatorcontrib><creatorcontrib>Chua, Joelle</creatorcontrib><creatorcontrib>Nguyen, Phuong H D</creatorcontrib><creatorcontrib>Lim, Chun J</creatorcontrib><creatorcontrib>Wasser, Martin</creatorcontrib><creatorcontrib>Hazirah, Sharifah N</creatorcontrib><creatorcontrib>Lim, Tony K H</creatorcontrib><creatorcontrib>Leow, Wei Qiang</creatorcontrib><creatorcontrib>Loh, Tracy Jiezhen</creatorcontrib><creatorcontrib>Wan, Wei Keat</creatorcontrib><creatorcontrib>Pang, Yin Huei</creatorcontrib><creatorcontrib>Soon, Gwyneth</creatorcontrib><creatorcontrib>Cheow, Peng Chung</creatorcontrib><creatorcontrib>Kam, Juinn Huar</creatorcontrib><creatorcontrib>Iyer, Shridhar</creatorcontrib><creatorcontrib>Kow, Alfred</creatorcontrib><creatorcontrib>Dan, Yock Young</creatorcontrib><creatorcontrib>Bonney, Glenn K</creatorcontrib><creatorcontrib>Chung, Alexander</creatorcontrib><creatorcontrib>Goh, Brian K P</creatorcontrib><creatorcontrib>Chow, Pierce K H</creatorcontrib><creatorcontrib>Albani, Salvatore</creatorcontrib><creatorcontrib>Zhai, Weiwei</creatorcontrib><creatorcontrib>Ouyang, John F</creatorcontrib><creatorcontrib>Toh, Han Chong</creatorcontrib><creatorcontrib>Chew, Valerie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hepatology communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nasir, N Jannah M</au><au>Chuah, Samuel</au><au>Shuen, Timothy</au><au>Prawira, Aldo</au><au>Ba, Rebecca</au><au>Lim, Mei Chee</au><au>Chua, Joelle</au><au>Nguyen, Phuong H D</au><au>Lim, Chun J</au><au>Wasser, Martin</au><au>Hazirah, Sharifah N</au><au>Lim, Tony K H</au><au>Leow, Wei Qiang</au><au>Loh, Tracy Jiezhen</au><au>Wan, Wei Keat</au><au>Pang, Yin Huei</au><au>Soon, Gwyneth</au><au>Cheow, Peng Chung</au><au>Kam, Juinn Huar</au><au>Iyer, Shridhar</au><au>Kow, Alfred</au><au>Dan, Yock Young</au><au>Bonney, Glenn K</au><au>Chung, Alexander</au><au>Goh, Brian K P</au><au>Chow, Pierce K H</au><au>Albani, Salvatore</au><au>Zhai, Weiwei</au><au>Ouyang, John F</au><au>Toh, Han Chong</au><au>Chew, Valerie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma</atitle><jtitle>Hepatology communications</jtitle><addtitle>Hepatol Commun</addtitle><date>2024-09-01</date><risdate>2024</risdate><volume>8</volume><issue>9</issue><issn>2471-254X</issn><eissn>2471-254X</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins</pub><pmid>39167427</pmid><doi>10.1097/HC9.0000000000000508</doi><orcidid>https://orcid.org/0000-0002-5617-0936</orcidid><orcidid>https://orcid.org/0000-0003-3700-9036</orcidid><orcidid>https://orcid.org/0000-0001-9305-7652</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Hepatology communications, 2024-09, Vol.8 (9) |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - immunology Carcinoma, Hepatocellular - mortality Chemokine CCL20 - genetics Down-Regulation GATA4 Transcription Factor - genetics Gene Expression Regulation, Neoplastic Humans Immune Tolerance Liver Neoplasms - genetics Liver Neoplasms - immunology Liver Neoplasms - mortality Liver Neoplasms - pathology Male Myeloid-Derived Suppressor Cells - immunology Original T-Lymphocytes, Regulatory - immunology Tumor Microenvironment - immunology |
| title | GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma |
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