Faculty, Staff and Student Publications
IRF1 Regulates Self-Renewal and Stress Responsiveness to Support Hematopoietic Stem Cell Maintenance
Publication Date
5-9-2023
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority 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 antifibrotic 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
Keywords
Humans, Carcinoma, Hepatocellular, Liver Neoplasms, Non-alcoholic Fatty Liver Disease, CD8-Positive T-Lymphocytes, Losartan, Liver Cirrhosis, NASH-driven HCC, anti-PD-1, losartan, liver fibrosis
DOI
10.1073/pnas.2300706120
PMID
37126700
PMCID
\PMC10175751
PubMedCentral® Posted Date
5-1-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons