Perilipin 5 as mediator of high-fat diet-induced hepatocellular carcinoma immune escape by stabilization of PD-L1 expression.

Abstract

e14600 Background: Obesity is a significant risk factor for hepatocellular carcinoma (HCC), but the precise mechanisms are unclear. Perilipin 5 (PLIN5) is crucial for lipid droplet synthesis, influences gut microbiota, and is pivotal in HCC progression. PLIN5 also plays a key role in Non-alcoholic Fatty Liver Disease (NAFLD)-induced HCC, with deletion reducing steatosis and modulating immune response and lipid metabolism. Unraveling these pathways could lead to novel therapeutic targets and preventive strategies, improving patient outcomes and reducing the global burden of HCC. Methods: Our study analyzed the effect of PLIN5 on the immune microenvironment of hepatocellular carcinoma in high-fat diet mice by flow cytometry and single-cell sequencing. In addition, we explored the specific mechanism by using Western blotting, immunohistochemistry, and other methods. Results: We found high-fat diet can induce the expression of ligand programmed cell death receptor 1 (PD-L1) in HCC cells both in vitro and in vivo . Perilipin 5 (PLIN5) is a key protein involved in lipid droplet synthesis and is positively correlated with the expression of PD-L1 in tumor tissues of HCC patients. Mechanistically, PLIN5 inhibits lysosomal dependent degradation of PD-L1 and increases the level of PD-L1 palmitoylation at C272A. In addition, small interfering RNA screening identified palmitoyltransferase 8 (DHHC8) as the main regulator of PLIN5 driven PD-L1 palmitoylation. Immunospectrum analysis showed that PLIN5 inhibition reduced the PD-L1 protein in HCC cells and promoted the infiltration of tumor infiltrating lymphocytes (TIL), which significantly improved the efficacy of anti-PD-L1 therapy in mouse HCC models. Conclusions: These findings emphasize the crucial role of PLIN5 in promoting tumor evasion of high-fat diet mediated immune surveillance, and identify PLIN5 could be regarded as a latent prognostic marker and a new target for cancer immunological therapy, particularly for HCC patients on a long-term high-fat diet.