Journal Article

DKFZ-2025-01518

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting Treg-fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma.

Prawira, A. ; Xu, H. ; Mei, Y. ; Nasir, N. J. M. ; Reolo, M. J. Y. ; Otsuka, M. ; Leow, W. Q. ; Rahbari, M.DKFZ* ; Chen, Z.DKFZ* ; Weerasooriya, M. ; Abdullah, L. B. ; Wu, J. ; Hazirah, S. N. ; Wasser, M. ; Chung, A. ; Goh, B. K. ; Chow, P. K. ; Albani, S. ; Lee, J. ; Lim, T. K. H. ; Zhai, W. ; Dan, Y. Y. ; Goh, G. B. ; Heikenwälder, M.DKFZ* ; Zhang, Y. ; Dasgupta, R. ; Tai, W. M. D. ; Liu, H. ; Chen, J. ; Chew, V.

2025
BMJ Publishing Group London

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Please use a persistent id in citations: doi:10.1136/gutjnl-2025-335084

Abstract: Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC), a rising global challenge, is characterised by unique tumour microenvironment (TME) adaptations.This study investigates the immune microenvironment and interactions driving immunosuppression and potential resistance to immunotherapy in SLD-HCC.We employed single-cell transcriptomics, cytometry by time-of-flight (CyTOF) and two independent spatial transcriptomics platforms to study the TME of 22 SLD-HCC and 31 non-SLD-HCC cases. Findings were further validated using multiplex immunohistochemistry in an independent cohort of 103 patients, an HCC model and an immunotherapy-treated patient cohort to evaluate clinical relevance.Our findings revealed significant alterations in immune and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs), suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. CyTOF revealed a cold, immunosuppressive TME with reduced CD8+ T cells and increased Tregs. Spatial transcriptomics further highlighted distinct Treg-CAF clusters localised at tumour margins, suggesting a spatially organised immunosuppressive niche. Mechanistically, tumour necrosis factor superfamily member 14 (TNFSF14)-tumour necrosis factor receptor superfamily member 14 (TNFRSF14)-mediated Treg-CAF interaction was identified as a critical driver of immunotherapy resistance in SLD-HCC. Blocking TNFRSF14 in an HCC model fed with a high-fat diet resulted in reduced Tregs, increased active CD8+ and memory CD4+ T cells, and a synergistic effect with anti-programmed cell death protein 1 therapy to enhance antitumour immunity and overcome immunotherapy resistance in SLD-HCC.This study uncovers critical immune and metabolic adaptations in SLD-HCC, identifying TNFSF14-TNFRSF14 signalling as a key driver of immunotherapy resistance. Targeting this signalling axis enhances antitumour immunity and improves immunotherapy efficacy, offering a promising therapeutic strategy for SLD-HCC.

Keyword(s): CELLULAR IMMUNITY ; HEPATOCELLULAR CARCINOMA ; IMMUNOREGULATION ; IMMUNOTHERAPY ; LIVER IMMUNOLOGY

Note: epub

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Contributing Institute(s):

1. Chronische Entzündung und Krebs (D440)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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