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

作者：Xin Xing, Shi-Qi Yin, Xiaqing Li, Hui Li, Hailong Ma, Aziguli Tulamaiti, Shu-Yu Xiao, Yu‐Tong Liu, Hao Zhang, Zhigang Zhang, Yan-Miao Huo, Xiao-Mei Yang, Yuan‐Han Yang, Xueli Zhang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010908 · 被引用次数：10 · 研究领域：Immunotherapy and Immune Responses、Cancer Immunotherapy and Biomarkers、T-cell and B-cell Immunology

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 ...