miRNA-146a protects mice from hepatocellular carcinoma by suppressing age-associated CD8+ T-cells 2715

Abstract Description Liver cancer is a major cause of cancer-related death globally, with Hepatocellular Carcinoma (HCC) representing up to 90% of primary liver cancers. Our lab and others have shown that the micro-RNA miR-146a protects mice from HCC-predisposing factors such as diet-induced obesity, fatty liver, and chronic inflammation. Our recent work using a mouse model of HCC demonstrates that in the absence of miR-146a, mice develop significantly more HCC tumors than Wt mice. Additionally, this increased tumor phenotype is rescued in miR-146a KO mice by co-deletion of the chemokine CCL5, a target of miR-146a in humans. Mechanistically, our data indicate that in the absence of miR-146a, a subpopulation of T-cells, termed age-associated CD8+ T-cells (Taa), significantly expand and secrete high levels of the chemokine CCL5. This leads to the recruitment of monocytic myeloid-derived suppressor cells (M-MDSCs), creating a tumor-promoting environment. Also of interest, the deletion of CCL5 did not reduce the metabolic disease that occurs in miR-146a -/- mice, suggesting that miR-146a regulates parallel pathways involved in obesity vs. HCC immunity. Taken together, these findings highlight a host protective role for miR-146a through its suppression of a unique subtype of CD8+ T-cells that promote HCC growth. Findings here will pave the way for improved immunotherapies to combat HCC in the future. Funding Sources Supported by NIH 5R01AG079477-03 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)