MAFLD reduces the efficacy of AFP peptide vaccination in murine liver cancer 4235

Abstract Description Introduction Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often occurs in the setting of metabolic dysfunction-associated fatty liver disease (MAFLD). Alpha-fetoprotein (AFP) is a biomarker that is often elevated in HCC. AFP degradation products are recognized by CD8 T Cells and can be used therapeutically as vaccines in mouse HCC models. In this study, we investigated whether the presence of MAFLD reduces AFP-specific CD8+ T cells in HCC. Methods We induced MAFLD-associated HCC through the hydrodynamic tail vein injection (HDTVi) of AKT/NRAS plasmids. The mice were primed with the AFP lentivirus followed by IV boost with the AFP[499-506] modified peptide, adjuvant, and checkpoint inhibitor. Separately, we induced MAFLD in mice through a methionine/choline-deficient (MCD) diet. The presence of TAS CD8+ T cells in MAFLD mice was detected using an AFP499-loaded tetramer. Results The presence of MAFLD in the RAS/AKT model of HCC correlated with resistance to treatment with AFP499 vaccine plus checkpoint inhibitors. In mice fed MCD, there was a significant reduction of AFP499 tetramer positive CD8 T cells compared to the control group. Additionally, a significant increase in exhaustion markers expressed on AFP tetramer positive CD8+ T cells was observed with MCD. Conclusion The presence of MAFLD reduces AFP-specific T cell generation and efficacy in HCC murine models, suggesting a mechanism of cancer vaccine resistance in MAFLD. Funding Sources National Institute On Minority Health And Health Disparities of the National Institutes of Health under Award Number U54MD007601 (Ola HAWAII), The Chun Foundation, Andrew and Mary Weinberg Foundation Topic Categories Vaccines and Immunotherapy (VAC)