MicroRNA-146a protects against hepatocellular carcinoma through suppression of CCL5

The microRNA miR-146a regulates several aspects of chronic inflammation, including the hepatocellular carcinoma (HCC) risk factor, steatohepatitis. Here, we find that loss of miR-146a leads to significantly increased tumor burden over a 9-month timeframe in a mouse model of HCC. Notably, this miR-146a-/- phenotype is most pronounced in females, who are typically not sensitive to this model. Mechanistically, we identified increases in dysfunctional CD8+ T cells that express high levels of CCL5 and resemble Age-Associated T (Taa) cells, as well as elevated levels of myeloid cells with a myeloid-derived suppressor cell (MDSC) phenotype, a class of myeloid cells that suppresses tumor immunity. Deletion of Ccl5 from miR-146a-deficient mice returned tumor growth and the aberrant myeloid cell populations to wild-type (WT) levels. Surprisingly, deletion of Ccl5 did not rescue the gross metabolic phenotype observed in miR-146a-/- mice subjected to HCC induction, indicating that miR-146a plays an independent role in regulating HCC and metabolic disease. Taken together, this work reveals a critical host-protective role for miR-146a in HCC that is mechanistically dependent on CCL5 and wherein tumor burden correlates with two suppressive immune populations, providing an impetus for targeting these pathways to combat HCC. Further, the correlations with tumor burden and Taa cells suggest that aging may increase HCC risk through the accumulation of CCL5-expressing Taa cells.