{"doi":"10.61440/jmdr.2025.v2.09","title":"Immunoprofiling of Alcohol-Activated Hepatic Stellate Cells Reveals Mechanisms of Immune Evasion Through NK/T Lymphocyte Checkpoint Signaling","abstract":"Background: Chronic heavy alcohol consumption induces the pathogenic activation of hepatic stellate cells (HSC) and their conversion into myofibroblasts (Myo), which together comprise a central disease hub. Clinical successes of immunotherapy in targeting pre-specified cell populations has suggested the possibility of harnessing the immune system to target and eliminate aHSC/Myo, however aHSC evade immune surveillance through mechanisms that remain poorly understood. Methods: We utilized a combination of FACS profiling of HSC surface-expressed immunomodulatory ligands, in vitro cytotoxicity assays, and scRNA-seq profiling of liver non-parenchymal cells to assess the impact of immunotherapy on HSC/Myo and immune cell populations. Results: In a mouse model of alcohol-induced liver damage, blocking CTLA-4, TIGIT, and PD-1 checkpoints enhanced immune targeting of hepatic cells. However, this did not reduce fibrosis or improve liver function. Single-cell analysis showed the treatment increased hepatic infiltration of NK and T cells while decreasing immunosuppressive Treg. However, engagement of PD-1 and TIGIT checkpoints also failed to ameliorate fibrosis or liver function. These findings suggest that while combined checkpoint blockade alters the hepatic immune landscape, it is insufficient as a standalone therapy to reverse alcoholrelated liver fibrosis. Conclusions: Immunotherapeutic modalities that enable precision targeting of HSC/Myo may be necessary to achieve therapeutic gains.","journal":null,"year":2025,"id":587452,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":306859,"name":"Yibu Chen","orcid":"0000-0002-7889-6850","position":1,"is_corresponding":false},{"id":236690,"name":"Subarna Biswas","orcid":"0000-0003-1868-3500","position":2,"is_corresponding":false},{"id":987700,"name":"Douglas E. Feldman","orcid":"0000-0003-0659-0788","position":3,"is_corresponding":false},{"id":1503408,"name":"Alexander Kessler","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:59:39.958043Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}