B4GALT5 inhibits CD8(+) T-cell response by downregulating MHC-I level through ERAD pathway in PDAC.

BACKGROUND: Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic target. METHODS: We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8(+) T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) levels. RESULTS: Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8(+) T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8(+) T cells. CONCLUSIONS: B4GALT5 impairs CD8(+) T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.