IDDF2023-ABS-0230 The role of aberrant N-Glycan branching regulated by MGAT4B in anti-tumor immunity in hepatocellular carcinoma

BackgroundIn hepatocellular carcinoma (HCC), glycosylation patterns are often altered, leading to the abnormal expression of specific glycoproteins and glycan structures, as a result impacting biological processes such as signal transduction and immune escape. N-acetylglucosaminyltransferases-IVb (MGAT4B) specifically adds N-acetylglucosamine (GlcNAc) to the beta-1,4-linked mannose residues in complex-type N-linked glycans of glycoproteins. However, the activity of MGAT4B during metabolic dysfunction of the liver and the glycosylated target of mgat4b has not been reported. And the function of MGAT4B in the diversity of the tumor immune microenvironment is unclear.MethodsWe first analyzed the expression of glycosylation-related genes profile associated with liver metabolic disorders in the TCGA public database. The expression difference between liver cancer and adjacent tumor tissues and the correlations of the expression levels in liver cancer with clinical pathological characteristics and prognosis were then validated via in-house clinical samples. Oncogene-driven murine HCC models were carried out to assess the changing of N-Glycan and the immune environment by regulating mgat4b. Moreover, the alteration of the glycosylation of immune checkpoints in tumor cells under the regulation of MGAT4B was evaluated. The effects of fatty acid or UDP-GlcNAc on the expression and activity of MGAT4B were verified in vitro.ResultsRT-qPCR, WB, and IHC proved MGAT4B was more highly overexpressed in HCC tumor tissues than tumor-adjacent tissues. The Kaplan–Meier analysis verified that the high expression of MGAT4B was related to poor overall survival (p < 0.01) and was associated with a bad prognosis in TCGA iCluster 1 with an ‘immune low’ signature and an activated WNT-β-catenin pathway. The activity of MGAT4B was sensitive to the level of fatty acids and UDP-GlcNAc. In the mouse hepatocellular carcinoma model driven by mutated β-catenin, mgat4b intervention mainly altered the recruitment of B lymphoid cells, myeloid-derived suppressor cells (MDSCs), and the function of effector T cells.ConclusionsThe activation of MGAT4B contributes to the metabolic dysfunction of the liver. Targeting the MGAT4B or associated glycosylated targets could be a promising approach to increase the immune response for HCC.