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Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.
Zhao, Liang; Pang, Yizhen; Zhou, Yangfan; Chen, Jianhao; Fu, Hao; Guo, Wei; Xu, Weizhi; Xue, Xin; Su, Guoqiang; Sun, Long; Wu, Hua; Zhang, Jingjing; Wang, Zhanxiang; Lin, Qin; Chen, Xiaoyuan; Chen, Haojun.
Afiliación
  • Zhao L; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Pang Y; Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore.
  • Zhou Y; Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Chen J; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Fu H; Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore.
  • Guo W; Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Xu W; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Xue X; Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Su G; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Sun L; Department of Colorectal Tumor Surgery, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Wu H; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Zhang J; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Wang Z; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Lin Q; Department of Cardiothoracic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
  • Chen X; Department of Colorectal Tumor Surgery, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • Chen H; Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Signal Transduct Target Ther ; 9(1): 142, 2024 Jun 03.
Article en En | MEDLINE | ID: mdl-38825657
ABSTRACT
Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 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 studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-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 rechallenge. Immunohistochemistry, 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 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Puntos de Control Inmunológico Límite: Animals / Humans Idioma: En Revista: Signal Transduct Target Ther Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Puntos de Control Inmunológico Límite: Animals / Humans Idioma: En Revista: Signal Transduct Target Ther Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido