GATA4 Downregulation Enhances CCL20-mediated Immunosuppression in Hepatocellular Carcinoma

Overview

Journal Hepatol Commun

Specialty Gastroenterology

Date 2024 Aug 21

PMID 39167427

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

Affiliations

Soon will be listed here.

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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