Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

作     者：Liang Zhao Yizhen Pang Yangfan Zhou Jianhao Chen Hao Fu Wei Guo Weizhi Xu Xin Xue Guoqiang Su Long Sun Hua Wu Jingjing Zhang Zhanxiang Wang Qin Lin Xiaoyuan Chen Haojun Chen Liang Zhao;Yizhen Pang;Yangfan Zhou;Jianhao Chen;Hao Fu;Wei Guo;Weizhi Xu;Xin Xue;Guoqiang Su;Long Sun;Hua Wu;Jingjing Zhang;Zhanxiang Wang;Qin Lin;Xiaoyuan Chen;Haojun Chen

作者机构：Department of Nuclear Medicine and Minnan PET CenterXiamen Key Laboratory of RadiopharmaceuticalsThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamenChina Departments of Diagnostic RadiologySurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingaporeSingapore Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Department of Radiation OncologyXiamen Cancer CenterXiamen Key Laboratory of Radiation OncologyThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamenChina Department of Colorectal Tumor SurgeryXiamen Cancer CenterXiamen Key Laboratory of Radiation OncologyThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamenChina Department of Cardiothoracic SurgeryZhongda HospitalSchool of MedicineSoutheast UniversityNanjingChina Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Department of Neurosurgery and Department of NeuroscienceFujian Key Laboratory of Brain Tumors Diagnosis and Precision TreatmentXiamen Key Laboratory of Brain Centerthe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamenChina Institute of Molecular and Cell BiologyAgency for ScienceTechnology and Research(A*STAR)SingaporeSingapore Xiamen Key Laboratory of Rare Earth Photoelectric Functional MaterialsXiamen Institute of Rare Earth MaterialsHaixi InstituteChinese Academy of SciencesXiamenChina 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2024年第9卷第7期

页      面：2936-2952页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：funded by the National Natural Science Foundation of China(82071961,82272037) Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Young Scholars in Fujian(2021ZQNZD016) Fujian Natural Science Foundation for Distinguished Young Scholars(2022D005) Key Medical and Health Projects in Xiamen(grant number 3502Z20209002) Xiamen Key Laboratory of Radiation Oncology,Xiamen Clinical Research Center for Head and Neck Cancer,and 2021 National Clinical Key Specialty,(Oncology,grant number 3210013) The National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine) National Medical Research Council(MOH-001388-00,CG21APR1005) Singapore Ministry of Education(MOE-000387-00) National Research Foundation(NRF-000352-00) 

主　　题：immunity retention holds 

摘      要：Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor *** radionuclide therapy delivers radiation directly to tumor ***1004 is a fibroblast activation protein(FAP)-targeting radiopharmaceutical,conjugated with the albumin binder Evans Blue,which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical ***,we demonstrate that^(68)Ga/^(177)Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor *** therapy with^(177)Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor *** combination of^(177)Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice,with mice showing 100%tumor rejection upon ***,single-cell RNA sequencing(scRNA-seq),and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication,CD8^(+)T-cell activation and expansion,M1 macrophage counts,antitumor activity of neutrophils,and T-cell receptor diversity.A preliminary clinical study demonstrated that^(177)Lu-LNC1004 was well-tolerated and effective in patients with refractory ***,scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade *** was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell *** conclusion,our data supported the efficacy of immunotherapy combined with^(177)Lu-LNC1004 for cancer patients with FAP-positive tumors.