{"doi":"10.1101/2023.03.05.531188","title":"Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells","abstract":"Abstract Although viral hepatocellular carcinoma (HCC) is declining, non-viral HCC, which often is the end-stage of non-alcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICI) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a small portion of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell mediated tumor regression and postulated that anti-fibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1 induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8 + T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with inhibition of TGF-β receptor signaling, collagen deposition and depletion of immunosuppressive fibroblasts. Significance Immune checkpoint inhibitors are used in HCC treatment but overall response rates for single agent PD-1/PD-L1 blockers have remained stubbornly low. Using a mouse model of NASH-driven HCC, we show that co-treatment with the safe and inexpensive angiotensin II receptor inhibitor losartan substantially enhanced anti-PD-1 triggered HCC regression. Although losartan did not influence the reinvigoration of exhausted CD8 + T cells it considerably enhanced their intratumoral invasion, which we postulated to be compromised by peritumoral fibrosis. Indeed, the beneficial effect of losartan correlated with inhibition of TGF-β signaling and collagen deposition, and depletion of immunosuppressive fibroblasts. Losartan should be evaluated for its adjuvant activity in HCC patients undergoing PD-1/PD-L1 blocking therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392233,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1032417,"name":"Yahui Zhu","orcid":"0000-0001-9444-5454","position":1,"is_corresponding":false},{"id":1032861,"name":"Maiya Lee","orcid":null,"position":2,"is_corresponding":false},{"id":992562,"name":"Albert Nguyen","orcid":"0000-0001-8724-7476","position":3,"is_corresponding":false},{"id":1032862,"name":"Nicolas T. Ryujin","orcid":null,"position":4,"is_corresponding":false},{"id":637786,"name":"Jian Yu Huang","orcid":"0000-0003-3012-4592","position":5,"is_corresponding":false},{"id":911594,"name":"Shadi Chamseddine","orcid":"0000-0001-7715-0689","position":6,"is_corresponding":false},{"id":419794,"name":"Lianchun Xiao","orcid":"0000-0003-0972-2766","position":7,"is_corresponding":false},{"id":573501,"name":"Yehia I. Mohamed","orcid":"0000-0002-5192-3804","position":8,"is_corresponding":false},{"id":54196,"name":"Ahmed O. Kaseb","orcid":"0000-0002-9491-0587","position":9,"is_corresponding":false},{"id":233466,"name":"Michael Karin","orcid":"0000-0002-2758-6473","position":10,"is_corresponding":false},{"id":233455,"name":"Shabnam Shalapour","orcid":"0000-0002-4743-3706","position":11,"is_corresponding":false},{"id":1037222,"name":"Li Gu","orcid":"0000-0001-9508-5673","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:18:52.232318Z","pmid":"36945365","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":[]}