GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma.

IF 8.3 2区材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Applied Materials & Interfaces Pub Date : 2024-08-19 eCollection Date: 2024-09-01 DOI:10.1097/HC9.0000000000000508

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

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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.

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GATA4 下调会增强 CCL20 介导的肝细胞癌免疫抑制。

背景：肝细胞癌（HCC）是一种致命的癌症，全球死亡率很高，GATA结合蛋白4（GATA4）的下调被认为与HCC的进展有关。方法：根据 GATA4 RNA 相对于邻近非肿瘤肝组织的表达情况，将 HCC 肿瘤样本分为 "低 "和 "正常/高 "两类。结果：GATA4低表达肿瘤和GATA4正常/高表达肿瘤的免疫图谱通过飞行时间细胞计数法、大量/空间转录组学分析进行了分析，并通过多重免疫荧光进行了验证：结果：GATA4低的肿瘤富集了衰竭性程序性细胞死亡蛋白1+ T细胞、免疫抑制性调节性T细胞、髓源抑制细胞和巨噬细胞，突显了GATA4下调对免疫抑制的影响。空间和大体转录组分析显示，GATA4与HCC中C-C Motif Chemokine Ligand 20（CCL20）的表达呈负相关。GATA4 的过表达证实了 CCL20 是一个下游靶点，有助于形成免疫抑制性肿瘤微环境，这一点从 CCL20 高的肿瘤中调节性 T 细胞和髓源性抑制细胞的增加可以得到证明。最后，GATA4表达的降低和CCL20表达的升高与HCC患者较差的总生存率有关，说明它们在肿瘤进展中的作用：我们的研究揭示了 GATA4 的下调导致了免疫抑制微环境的形成，而这种微环境是由 CCL20 介导的调节性 T 细胞和髓源性抑制细胞在 HCC 中的富集所驱动的。这些发现强调了 GATA4 下调在促进免疫抑制和 HCC 进展中的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Materials & Interfaces 工程技术-材料科学：综合

CiteScore

16.00

自引率

6.30%

发文量

4978

审稿时长

1.8 months

期刊介绍： ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.