B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma

Invasive adenocarcinoma (IAC), which is typically preceded by minimally invasive adenocarcinoma (MIA), is the dominant pathological subtype of early-stage lung adenocarcinoma (LUAD). Identifying the molecular events underlying the progression from MIA to IAC may provide a crucial perspective and boost the exploration of novel strategies for early-stage LUAD diagnosis and treatment.

B4GALT1 is a critical molecule in the development of early-stage LUAD and may be a novel target for LUAD intervention and immunotherapy.

Transcriptome sequencing of four pairs of MIA and IAC tumours obtained from four multiple primary lung cancer patients was performed to screen out beta-1,4-galactosyltransferase1 (B4GALT1). Function and mechanism experiments in vitro and in vivo were performed to explore the regulatory mechanism of B4GALT1-mediated immune evasion by regulating programmed cell death ligand 1 (PD-L1).

B4GALT1, a key gene involved in N-glycan biosynthesis, was highly expressed in IAC samples. Further experiments revealed that B4GALT1 regulated LUAD cell proliferation and invasion both in vitro and in vivo and was related to the impaired antitumour capacity of CD8 + T cells. Mechanistically, B4GALT1 directly mediates the N-linked glycosylation of PD-L1 protein, thus preventing PD-L1 degradation at the posttranscriptional level. In addition, B4GALT1 stabilized the TAZ protein via glycosylation, which activated CD274 at the transcriptional level. These factors lead to lung cancer immune escape. Importantly, inhibition of B4GALT1 increased CD8 + T-cell abundance and activity and enhanced the antitumour immunity of anti-PD-1 therapy in vivo.