Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy  

作　　者：Xinyi Cao Zhihuang Hu Xiangying Sheng Zhenyu Sun Lijun Yang Hong Shu Xiaojing Liu Guoquan Yan Lei Zhang Chao Liu Ying Zhang Huijie Wang Haojie Lu 

机构地区：[1]Institutes of Biomedical Sciences and Shanghai Cancer Center,Fudan University,Shanghai 200032,China [2]Department of Laboratory Medicine,Huashan Hospital,Fudan University,Shanghai 200040,China [3]Department of Medical Oncology,Fudan University Shanghai Cancer Center,Shanghai 200032,China [4]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China [5]Department of Chemistry,Fudan University,Shanghai 200433,China [6]Department of Clinical Laboratory,Guangxi Medical University Cancer Hospital,Nanning 530021,China [7]Beijing Advanced Innovation Center for Precision Medicine,Beihang University,Beijing 100083,China [8]NHC Key Laboratory of Glycoconjugates Research,Fudan University,Shanghai 200032,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第8期1099-1107,共9页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Key Research and Development Program of China(No.2022YFC3400800);the National Natural Science Foundation of China(Nos.21974025 and 82121004);the Shanghai Projects(Nos.22142202400 and 22DZ2291700);the Greater Bay Area Institute of Precision Medicine(No.IPM2021C005).

摘　　要：Immune checkpoint inhibitors(ICIs)targeting programmed cell death 1/programmed cell death ligand-1(PD-1/PDL1)have significantly prolonged the survival of advanced/metastatic patients with lung cancer.However,only a small proportion of patients can benefit from ICIs,and clinical management of the treatment process remains challenging.Glycosylation has added a new dimension to advance our understanding of tumor immunity and immunotherapy.To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins,a series of serum samples from 12 patients with metastatic lung squamous cell carcinoma(SCC)and lung adenocarcinoma(ADC),collected before and during ICIs treatment,are firstly analyzed with mass-spectrometrybased label-free quantification method.Second,a stratification analysis is performed among anti-PD-1/PD-L1 responders and non-responders,with serum levels of glycopeptides correlated with treatment response.In addition,in an independent validation cohort,a large-scale site-specific profiling strategy based on chemical labeling is employed to confirm the unusual characteristics of IgG N-glycosylation associated with anti-PD-1/PD-L1 treatment.Unbiased label-free quantitative glycoproteomics reveals serum levels’alterations related to anti-PD-1/PD-L1 treatment in 27 out of 337 quantified glycopeptides.The intact glycopeptide EEQFN177STYR(H3N4)corresponding to IgG4 is significantly increased during anti-PD-1/PD-L1 treatment(FC=2.65,P=0.0083)and has the highest increase in anti-PD-1/PD-L1 responders(FC=5.84,P=0.0190).Quantitative glycoproteomics based on protein puri fication and chemical labeling confirms this observation.Furthermore,obvious associations between the two intact glycopeptides(EEQFN177STYR(H3N4)of IgG4,EEQYN227STFR(H3N4F1)of IgG3)and response to treatment are observed,which may play a guiding role in cancer immunotherapy.Our findings could benefit future clinical disease management.

关 键 词：lung cancer PD-1/PD-L1 IMMUNOTHERAPY GLYCOPEPTIDE IGG 

分 类 号：R73[医药卫生—肿瘤]