Immunoprofiling of Alcohol-Activated Hepatic Stellate Cells Reveals Mechanisms of Immune Evasion through NK/T Lymphocyte Checkpoint Signaling

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Immunoprofiling of Alcohol-Activated Hepatic Stellate Cells Reveals Mechanisms of Immune Evasion through NK/T Lymphocyte Checkpoint Signaling

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1
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
2
Bioinformatics Service, Department of Health Sciences Libraries, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
3
Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
*
Authors to whom correspondence should be addressed.

Received: 31 July 2025 Accepted: 30 September 2025 Published: 10 October 2025

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© 2025 The authors. This is an open access article under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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Fibrosis 2025, 3(4), 10012; DOI: 10.70322/fibrosis.2025.10012
ABSTRACT: Chronic alcohol consumption induces the pathogenic activation of hepatic stellate cells (HSC) and their conversion into proliferative myofibroblasts (Myo), which together constitute a disease hub in alcohol-associated liver disease (AALD). While natural killer (NK) lymphocytes efficiently target early activated HSC and ameliorate liver fibrosis in mouse models of diet- and alcohol-induced liver disease, late-activated HSC evade immune surveillance. To gain insight into evasive resistance mechanisms, we profiled the expression of immunoregulatory ligands by HSC and showed that HSC dynamically express CD80, a B7-family ligand that suppresses NK and T cell responses. Using a mouse model of acute-on-chronic alcohol consumption, we show that combined blockade of the CTLA-4//TIGIT/PD-1 inhibitory checkpoints overcomes this resistance mechanism, promoting the selective elimination of activated HSC (aHSC)/Myo, yet fails to diminish fibrosis or ameliorate liver function. Single-cell transcriptome profiling of liver non-parenchymal cells revealed that checkpoint blockade promotes hepatic infiltration of pro-fibrotic Th1 and Th17 T cell subpopulations, while decreasing immunosuppressive Treg. Strikingly, antibody-directed engagement of the PD-1 and TIGIT checkpoints also fails to reduce fibrosis or improve liver function. Thus, selective targeting of aHSC/Myo may be necessary to achieve significant therapeutic benefit.
Keywords: AALD; Immunotherapy; Checkpoint; Hepatic stellate cell
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