AbstractImmunotherapy 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.

摘要免疫疗法彻底改变了癌症治疗，但缺乏可靠的治疗反应预测生物标志物仍然是一个挑战。α-1,6-甘露糖基糖蛋白6-β-N-乙酰氨基葡萄糖转移酶5（MGAT5）是复杂N-聚糖合成的关键调节剂，其失调与癌症进展有关。

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.

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的活性增加。然而，MGAT5在HNSCC中的具体作用仍不清楚。

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.

在这项研究中，我们发现与邻近的非肿瘤组织相比，HNSCC肿瘤中的PHA-L染色和MGAT5表达显着更高。使用基于质谱（MS）的糖蛋白组学方法，我们鉴定了MGAT5的163种潜在蛋白质底物。功能分析表明，MGAT5的蛋白质底物调节与T细胞增殖和活化相关的途径。

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.

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。nivolumab的治疗减轻了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治疗的反应有所改善。

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.

使用来自HNSCC细胞的纯化PD-L1和糖蛋白组学方法，我们进一步破译了N35和N200位点在PD-L1上携带大多数复杂的N-聚糖。我们的研究结果强调了MGAT5介导的分支N-聚糖在PD-L1上调节与免疫检查点受体PD-1相互作用的关键作用。

Consequently, we propose that MGAT5 could serve.

因此，我们建议MGAT5可以服务。

IntroductionHead and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with approximately 67,000 new patients annually [1]. Although surgical resection followed by adjuvant chemoradiotherapy is applied to all advanced HNSCC cancers, around 50% of patients relapse after primary treatment [2].

引言头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，每年约有67000名新患者（1）。虽然手术切除后辅助放化疗适用于所有晚期HNSCC癌症，但约50%的患者在初次治疗后复发（2）。

The recurrence after multidisciplinary treatment is often incurable, leading to a devastating prognosis [3]. Owing to the success of immunotherapy with the anti-programmed cell death protein 1 (PD-1) agents nivolumab and pembrolizumab, treatment options for recurrent and/or metastatic (R/M) HNSCC are no longer limited to platinum drugs and cetuximab [4,5,6,7].

多学科治疗后的复发通常是无法治愈的，导致毁灭性的预后（3）。。

Compared to traditional chemotherapeutic agents, immunotherapy has demonstrated higher efficacy and lower toxicity, providing great benefits for heavily treated patients. However, the response rate of single-agent immunotherapy is only 15–20%, and current clinical trials suggest combining immunotherapy with chemotherapy if PD-L1 expression in tumors is low [5].Programmed death ligand 1 (PD-L1) was discovered in 1999 and later known as an immune checkpoint molecule [8].

与传统的化疗药物相比，免疫疗法显示出更高的疗效和更低的毒性，为接受严重治疗的患者提供了巨大的益处。然而，单药免疫治疗的有效率仅为15-20%，目前的临床试验表明，如果肿瘤中PD-L1的表达较低，则将免疫治疗与化疗相结合[5]。程序性死亡配体1（PD-L1）于1999年被发现，后来被称为免疫检查点分子（8）。

Cancer cells express PD-L1 to interact with the PD-1 on T cells, resulting in inhibition of T cell activation [9]. Antibodies blocking PD-L1 or PD-1 gained unprecedented success and cured refractory cancers [9, 10]. These findings revolutionized cancer treatment and led to a Nobel Prize in Medicine in 2018 shared by Jim Allison and Tasuku Honjo.

癌细胞表达PD-L1与T细胞上的PD-1相互作用，从而抑制T细胞活化（9）。阻断PD-L1或PD-1的抗体取得了前所未有的成功，治愈了难治性癌症[9，10]。这些发现彻底改变了癌症治疗，并导致吉姆·埃里森（JimAllison）和TasukuHonjo（TasukuHonjo）于2018年获得诺贝尔医学奖。

However, there are still some challenges regarding immune check point inhibitors (ICIs). Firstly, while durable and complete treatment responses from ICIs are observed in some individuals, the majority of patients fail to respond. Secondly, reliable biomarkers predicting treatment response ar.

然而，关于免疫检查点抑制剂（ICI）仍然存在一些挑战。首先，虽然在一些个体中观察到ICI的持久和完整的治疗反应，但大多数患者没有反应。。

Data availability

数据可用性

The LC-MS/MS data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under the dataset identifier PXD045506. Other original contributions from this study are included in the article and supplementary materials. For further inquiries, please contact the corresponding author..

LC-MS/MS数据已通过PRIDE合作伙伴存储库以数据集标识符PXD045506保存在ProteomeXchange Consortium中。这项研究的其他原始贡献包括在文章和补充材料中。如需进一步查询，请联系通讯作者。。

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Download referencesAcknowledgementsWe thank Dr. Sung-Liang Yu and Dr. Wen-Hui Ku for assistance of VENTANA PD-L1 (SP263) assay and calculation of the tumor proportion score. We thank Elaine Keisha Johan for technical support. We are grateful for the technical support provided by the First and Eighth core lab, and the Sequencing and Biochemistry core, Department of Medical Research, National Taiwan University Hospital.

下载参考文献致谢我们感谢Sung Liang Yu博士和Wen Hui Ku博士对VENTANA PD-L1（SP263）测定和肿瘤比例评分计算的帮助。我们感谢Elaine Keisha Johan的技术支持。我们感谢第一和第八核心实验室以及国立台湾大学医院医学研究部测序和生物化学核心提供的技术支持。

This study was supported by the Ministry of Science and Technology, 111-2320-B-002 -019 -MY3 (MCH), 110-2314-B-002 -183 -MY3, 113-2314-B-002 -086 -MY3 (PJL), 110-2314-B-002 -182 -MY3, 113-2314-B-002 -087 -MY3 (MCL), and the National Health Research Institutes, NHRI-EX110-10909BC (MCL).Author informationAuthor notesThese authors contributed equally: Huai-Cheng Huang, Yen-Lin Huang, Yi-Ju Chen, Hsin-Yi Wu.Authors and AffiliationsDepartment of Oncology, National Taiwan University Hospital, Taipei, TaiwanHuai-Cheng HuangDepartment of Pathology, National Taiwan University Cancer Center, Taipei, TaiwanYen-Lin HuangInstitute of Chemistry, Academia Sinica, Taipei, TaiwanYi-Ju ChenInstrumentation Center, National Taiwan University, Taipei, TaiwanHsin-Yi WuDepartment of Medical Research, National Taiwan University Hospital, Taipei, TaiwanChia-Lang HsuDepartment of Medical Oncology, National Taiwan University Cancer Center, Taipei, TaiwanHsiang-Fong Kao & Bin-Chi LiaoDepartment of Pathology, National Taiwan University Hospital, Taipei, TaiwanMin-Shu HsiehGraduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, TaiwanNeng-Yu Lin & Min-Chuan HuangDepartment of Otolaryngology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, TaiwanYu-Hao LiaoDepartment of Otolaryngology, National Taiwan Univers.

这项研究得到了科学技术部111-2320-B-002-019-MY3（MCH），110-2314-B-002-183-MY3113-2314-B-002-086-MY3（PJL），110-2314-B-002-182-MY3113-2314-B-002-087-MY3（MCL）和国家卫生研究院NHRI-EX110-10909BC（MCL）的支持。作者信息作者注意到这些作者做出了同样的贡献：黄怀诚，黄延林，陈一菊，吴信义。作者和所属单位台北国立台湾大学医院肿瘤学系台北国立台湾大学癌症中心病理学系台北国立台湾大学化学研究所台北国立台湾大学医学研究所台湾国立台湾大学医院医学研究系台湾国立台湾大学肿瘤中心肿瘤医学系台湾国立台湾大学医院病理学系台湾国立台湾大学医院病理学系台湾国立台湾大学医院解剖与细胞生物学研究生院台湾国立台湾大学医学院台湾大学附属台湾大学医院新竹分院耳鼻咽喉科，台湾大学附属台湾大学新竹分院耳鼻咽喉科。

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PubMed Google ScholarContributionsStudy concepts: MCL, MCH, and PJL; Study design: MCL, HCH, YLH, YJC, and HYW; Data acquisition: HCH, YLH, YJC, HYW, CLH, HFK, BCL, MSH, NYL, YHL, HLC, CNC, TCC, CPW, TLY, MCH, MCL, and PJL; Quality control of data and algorithms: MCL, HCH, YLH, YJC, and HYW; Data analysis and interpretation: MCL, HCH, YLH, YJC, and HYW; Statistical analysis: MCL, HCH, YLH, YJC, and HYW; Manuscript preparation: MCL, HCH, YLH, YJC, and HYW; Manuscript review: MCL, HCH, YLH, YJC, HYW, MCH, and PJL.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献研究概念：MCL，MCH和PJL；研究设计：MCL，HCH，YLH，YJC和HYW；数据采集：HCH，YLH，YJC，HYW，CLH，HFK，BCL，MSH，NYL，YHL，HLC，CNC，TCC，CPW，TLY，MCH，MCL和PJL；数据和算法的质量控制：MCL，HCH，YLH，YJC和HYW；数据分析和解释：MCL，HCH，YLH，YJC和HYW；统计分析：MCL，HCH，YLH，YJC和HYW；稿件准备：MCL，HCH，YLH，YJC和HYW；手稿审查：MCL，HCH，YLH，YJC，HYW，MCH和PJL。。

Mei-Chun Lin.Ethics declarations

林美春.道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethical approval

道德认可

The acquisition of head and neck tumor tissues for this study was conducted in compliance with the guidelines and regulations set forth by the Institutional Review Board (IRB) of National Taiwan University Hospital in Taipei, Taiwan. The study adhered to the principles outlined in the Declaration of Helsinki, and it was assigned the IRB number 202011107RINA.

本研究的头颈部肿瘤组织的获取是根据台湾台北国立台湾大学医院机构审查委员会（IRB）制定的指南和规定进行的。这项研究遵循了《赫尔辛基宣言》中概述的原则，并被指定为IRB编号202011107RINA。

Additionally, all animal experiments performed during this study were carried out in accordance with the appropriate regulations governing animal experimentation. The research protocol was approved by the ethics committee and the Institutional Animal Care and Use Committee (IACUC) of the National Taiwan University College of Medicine in Taipei, Taiwan, under the IACUC No.

此外，本研究期间进行的所有动物实验均按照有关动物实验的适当规定进行。该研究方案经台湾台北国立台湾大学医学院伦理委员会和机构动物护理与使用委员会（IACUC）批准，IACUC编号为。

20180161..

20180161..

Informed consent

Written informed consents were obtained from all patients.

所有患者均获得书面知情同意书。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary figure and table legendsTable S1. Glycopeptides with potential β1,6-branched N-glycans in SAS cellsTable S2.

。补充信息补充数字和表格legendsTable S1。SAS细胞稳定S2中具有潜在β1,6-支链N-聚糖的糖肽。

Enriched pathways of potential MGAT5 substratesTable S3. Patient characteristicsFigure S1-S5Rights and permissions.

潜在MGAT5底物稳定S3的富集途径。患者特征图S1-S5权利和权限。

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Reprints and permissionsAbout this articleCite this articleHuang, HC., Huang, YL., Chen, YJ. et al. The branched N-glycan of PD-L1 predicts immunotherapy responses in patients with recurrent/metastatic HNSCC.

转载和许可本文引用本文Huang，HC。，黄，YL。，陈，YJ。PD-L1的分支N-聚糖预测复发/转移性HNSCC患者的免疫治疗反应。

Oncogenesis 13, 36 (2024). https://doi.org/10.1038/s41389-024-00532-3Download citationReceived: 24 May 2023Revised: 13 August 2024Accepted: 23 August 2024Published: 02 October 2024DOI: https://doi.org/10.1038/s41389-024-00532-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

肿瘤发生13,36（2024）。https://doi.org/10.1038/s41389-024-00532-3Download引文接收日期：2023年5月24日修订日期：2024年8月13日接受日期：2024年8月23日发布日期：2024年10月2日OI：https://doi.org/10.1038/s41389-024-00532-3Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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