Metabolic landscape of head and neck squamous cell carcinoma informs a novel kynurenine/Siglec-15 axis in immune escape  

作　　者：Xin-Yu Zhang Jian-Bo Shi Shu-Fang Jin Rui-Jie Wang Ming-Yu Li Zhi-Yuan Zhang Xi Yang Hai-Long Ma 

机构地区：[1]Department of Oral Maxillofacial-Head and Neck Oncology,Shanghai Ninth People’s Hospital,College of Stomatology,Shanghai Jiao Tong University School of Medicine,Shanghai,P.R.China [2]National Clinical Research Center for Oral Diseases,Shanghai,P.R.China [3]Shanghai Key Laboratory of Stomatology&Shanghai Research Institute of Stomatology,Shanghai,P.R.China [4]Department of Second Dental Center,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,College of Stomatology,Shanghai Jiao Tong University,Shanghai,P.R.China

出　　处：《Cancer Communications》2024年第6期670-694,共25页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:82303280,82072980,82272831,82272983,82172897,82203614;Science and Technology Daystar Program of Shanghai,Grant/Award Number:22QA1405300;Natural Science Foundation of Shanghai,Grant/Award Numbers:22ZR1436800,20ZR1447300;Young Talent Lift Project by the China Association for Science and Technology,Grant/Award Number:2020QNRC001;Shanghai Sailing Program,Grant/Award Number:22YF1421600;Young physicians collaborative innovation team of Shanghai Ninth People’s Hospital,Grant/Award Number:QC202004;The Innovative Research Team of High-level Local Universities in Shanghai,Grant/Award Numbers:SHSMU-ZDCX20212500,SHSMU-ZLCX20212300。

摘　　要：Background:Metabolic reprograming and immune escape are two hallmarksof cancer.However,how metabolic disorders drive immune escape in head andneck squamous cell carcinoma(HNSCC)remains unclear.Therefore,the aim ofthe present study was to investigate the metabolic landscape of HNSCC and itsmechanism of driving immune escape.Methods:Analysis of paired tumor tissues and adjacent normal tissues from69 HNSCC patients was performed using liquid/gas chromatography-mass spectrometry and RNA-sequencing.The tumor-promoting function of kynurenine(Kyn)was explored in vitro and in vivo.The downstream target of Kyn wasinvestigated in CD8^(+)T cells.The regulation of CD8+T cells was investigatedafter Siglec-15 overexpression in vivo.An engineering nanoparticle was establishedto deliver Siglec-15 small interfering RNA(siS15),and its association withimmunotherapy response were investigated.The association between Siglec-15and CD8^(+)programmed cell death 1(PD-1)^(+)T cells was analyzed in a HNSCCpatient cohort.Results:A total of 178 metabolites showed significant dysregulation in HNSCC,including carbohydrates,lipids and lipid-like molecules,and amino acids.Among these,amino acid metabolism was the most significantly altered,especiallyKyn,which promoted tumor proliferation and metastasis.In addition,most immune checkpoint molecules were upregulated in Kyn-high patientsbased on RNA-sequencing.Furthermore,tumor-derived Kyn was transferredinto CD8^(+)T cells and induced T cell functional exhaustion,and blockingKyn transporters restored its killing activity.Accroding to the results,mechanistically,Kyn transcriptionally regulated the expression of Siglec-15 via arylhydrocarbon receptor(AhR),and overexpression of Siglec-15 promoted immuneescape by suppressing T cell infiltration and activation.Targeting AhR in vivoreduced Kyn-mediated Siglec-15 expression and promoted intratumoral CD8^(+)Tcell infiltration and killing capacity.Finally,a NH_(2)-modified mesoporous silicananoparticle was designed to deliver siS15,which restored CD8^(+)T c

关 键 词：head and neck squamous cell carcinoma KYNURENINE Siglec-15 T cell exhaustion untargeted metabolomics 

分 类 号：R739.91[医药卫生—肿瘤]