With the popularization of lung cancer screening and the clinical application of computed tomography (CT), the number of detected pulmonary nodules has significantly increased, many of which are adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). After surgical resection, the 5-year survival rate of AIS and MIA is close to 100%, and the recurrence rate is 0%, while IAC does not have such good survival benefits.
Several professional societies have revised the classification of lung adenocarcinoma (LUAD) and its precursors, including the evolutionary spectrum from atypical adenomatous hyperplasia (AAH) to AIS, MIA, and finally IAC. Previous studies have described the genome, immune, and metabolic profiles of AIS, MIA, and IAC, which may contribute to the early detection and prevention of cancer. However, there is still a lack of in-depth insight into the exact molecular events behind the development trajectory of early LUAD from MIA to IAC.
Recently, researchers from the First Affiliated Hospital of Nanjing Medical University published an article on J Exp Clin Cancer Res entitled “B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma”, which revealed that B4GALT1 is a key molecule in the early onset of LUAD and may become a new target for LUAD intervention and immunotherapy.
(Yanan Cui et al. 2023)
Invasive adenocarcinoma (IAC) is the main pathological subtype of early lung adenocarcinoma (LUAD), which usually precedes minimally invasive adenocarcinoma (MIA). Identifying molecular events that progress from MIA to IAC may provide an important perspective and promote the exploration of new strategies for early diagnosis and treatment of LUAD.
In order to filter out β- 1, 4-neneneba galactosyltransferase 1 (B4GALT1) was used to sequence the transcriptome of four pairs of MIA and IAC tumors from four patients with multiple primary cancers. To explore the mechanism of B4GALT1 regulating immune escape by regulating programmed cell death ligand 1 (PD-L1) through in vitro and in vivo function and mechanism experiments.
The key gene B4GALT1 involved in N-polysaccharide biosynthesis is highly expressed in IAC samples. Further experiments have shown that B4GALT1 regulates the proliferation and invasion of LUAD cells both in vivo and in vitro, and is associated with impaired anti-tumor ability of CD8+T cells. Mechanically speaking, B4GALT1 directly mediates the N-linked glycosylation of PD-L1 protein, thereby preventing the degradation of PD-L1 at the post-transcriptional level.
In addition, B4GALT1 stabilized the TAZ protein through glycosylation, thereby activating CD274 at the transcriptional level. These factors lead to immune escape in lung cancer. Importantly, inhibiting B4GALT1 increases the abundance and activity of CD8+T cells and enhances anti-tumor immunity against PD-1 therapy in vivo.
In summary, based on a unique MPLC model, researchers have revealed that B4GALT1 promotes immune evasion and tumorigenesis in early LUAD, and discovered a new mechanism by which B4GALT1 regulates PD-L1 at the transcriptional level by stabilizing the TAZ protein and directly regulates PD-L1 at the post-translational level by modifying PD-L1. This study provides a theoretical basis for the application of B4GALT1 as a potential therapeutic target for LUAD.
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Reference
Yanan Cui et al. B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma. J Exp Clin Cancer Res. 2023 Jun 12;42(1):146. doi: 10.1186/s13046-023-02711-3.