Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
Duke-NUS Medical School, Singapore.
Hepatol Commun. 2024 Aug 19;8(9). doi: 10.1097/HC9.0000000000000508. eCollection 2024 Sep 1.
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.
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）的下调与 HCC 的进展有关。在这项研究中，我们研究了 GATA4 在塑造 HCC 免疫景观中的作用。
根据 HCC 肿瘤样本中 GATA4 RNA 相对于相邻非肿瘤肝组织的表达，将其分为“低”或“正常/高”。使用飞行时间流式细胞术、批量/空间转录组分析对 GATA4-低和 GATA4-正常/高肿瘤的免疫景观进行分析，并通过多重免疫荧光进行验证。
GATA4-低肿瘤中耗尽的程序性细胞死亡蛋白 1+T 细胞、免疫抑制性调节性 T 细胞、髓系来源的抑制性细胞和巨噬细胞富集，突出了 GATA4 下调对免疫抑制的影响。空间和批量转录组分析显示 GATA4 与 HCC 中 C-C 基序趋化因子配体 20（CCL20）的表达呈负相关。过表达 GATA4 证实 CCL20 是一个下游靶点，通过增加 CCL20-高肿瘤中的调节性 T 细胞和髓系来源的抑制性细胞，促进免疫抑制性肿瘤微环境。最后，GATA4 表达降低和 CCL20 表达升高与 HCC 患者总体生存较差相关，提示它们在肿瘤进展中的作用。
我们的研究表明，GATA4 下调导致 HCC 中调节性 T 细胞和髓系来源的抑制性细胞通过 CCL20 介导的富集而产生免疫抑制微环境。这些发现强调了 GATA4 减少在促进免疫抑制和 HCC 进展中的关键作用。
