Huang Huai-Cheng, Huang Yen-Lin, Chen Yi-Ju, Wu Hsin-Yi, Hsu Chia-Lang, Kao Hsiang-Fong, Liao Bin-Chi, Hsieh Min-Shu, Lin Neng-Yu, Liao Yu-Hao, Chen Hsin-Lin, Chen Chun-Nan, Chen Tseng-Cheng, Wang Cheng-Ping, Yang Tsung-Lin, Huang Min-Chuan, Lin Mei-Chun, Lou Pei-Jen
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan.
Oncogenesis. 2024 Oct 2;13(1):36. doi: 10.1038/s41389-024-00532-3.
Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.
免疫疗法彻底改变了癌症治疗方式，但缺乏可靠的治疗反应预测生物标志物仍是一项挑战。α-1,6-甘露糖基糖蛋白6-β-N-乙酰氨基葡萄糖基转移酶5（MGAT5）是复杂N-聚糖合成的关键调节因子，其失调与癌症进展相关。凝集素菜豆白细胞凝集素（PHA-L）特异性结合成熟的MGAT5产物。先前的研究表明，头颈部鳞状细胞癌（HNSCC）中PHA-L染色升高，这意味着MGAT5活性增加。然而，MGAT5在HNSCC中的具体作用仍不清楚。在本研究中，我们发现与相邻的非肿瘤组织相比，HNSCC肿瘤中PHA-L染色和MGAT5表达显著更高。使用基于质谱（MS）的糖蛋白质组学方法，我们鉴定出163种MGAT5的潜在蛋白质底物。功能分析表明，MGAT5的蛋白质底物调节与T细胞增殖和激活相关的途径。我们进一步发现，PD-L1是MGAT5的蛋白质底物之一，MGAT5的表达保护肿瘤细胞免受细胞毒性T淋巴细胞（CTL）杀伤。纳武单抗治疗减轻了MGAT5对CTL活性的保护作用。一致地，与MGAT5阴性肿瘤患者相比，MGAT5阳性肿瘤患者对免疫疗法的反应更好。使用从HNSCC细胞中纯化的PD-L1和糖蛋白质组学方法，我们进一步破译出N35和N200位点携带了PD-L1上大部分复杂N-聚糖。我们的研究结果突出了MGAT5介导的PD-L1上分支N-聚糖在调节与免疫检查点受体PD-1相互作用中的关键作用。因此，我们提出MGAT5可作为预测患者对抗PD-1治疗反应的生物标志物。此外，靶向PD-L1的N35和N200处的分支N-聚糖可能会导致新型诊断和治疗方法的开发。
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