Yu Long1,2,3, Xiaoying Lv1,2,3, Xiangming Song1,2,3, Fuqiang Shao1,2,3, Hao Ji1,2,3, Yirui Zhang4, Pengxin Qiao1,2,3, Qingyao Liu1,2,3, Xiaotian Xia1,2,3, Ping Lei4, Yongkang Gai5,6,7, Xiaoli Lan8,9,10. 1. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Ave 1277, Wuhan, 430022, Hubei Province, China. 2. Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China. 3. Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, 430022, China. 4. Department of Immunology, Basic Medical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. 5. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Ave 1277, Wuhan, 430022, Hubei Province, China. gykmail@hust.edu.cn. 6. Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China. gykmail@hust.edu.cn. 7. Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, 430022, China. gykmail@hust.edu.cn. 8. Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Ave 1277, Wuhan, 430022, Hubei Province, China. LXL730724@hotmail.com. 9. Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China. LXL730724@hotmail.com. 10. Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, 430022, China. LXL730724@hotmail.com.
Abstract
PURPOSE: γδ T cell-based immunotherapy has been rolled out as a promising treatment strategy for malignant tumors due to their potent anti-tumor cytotoxicity, ease of expansion, and unrestricted MHC feature. However, the dynamics and outcomes of γδ T cells in tumor sites are poorly understood. Reported strategies rely on ex vivo biolabeling, significantly limiting the application of γδ T cell molecular imaging. Herein, we investigated whether VLA-4 (very late antigen-4), a crucial component in the effective trafficking of lymphocytes, could serve as a biomarker to non-invasively visualize γδ T cells. METHODS: VLA-4-targeted tracer, 68 Ga-LLP2A, was evaluated in MDA-MB-231- and A549-bearing mice with adoptive transfer of γδ T cells by longitudinal PET/CT imaging. Imaging data were verified by ex vivo biodistribution studies, and the co-localization of CD3 and VLA-4 was validated by immunohistochemistry studies. RESULTS: 68 Ga-LLP2A showed high specificity to VLA-4-expressing γδ T cells in both in vitro and tumor-bearing mice with adoptive transfer of γδ T cells. Longitudinal PET imaging of 68 Ga-LLP2A in tumor-bearing mice with adoptive transfer of γδ T cells showed an increasing tumor tracer uptake, revealing the tumor-specific homing of γδ T cells. The presence of VLA-4-expressing γδ T cells in tumors was confirmed via histological analysis. CONCLUSION: To the best of our knowledge, we reported the first molecular probe, 68 Ga-LLP2A, for in vivo imaging of γδ T cells in live tumors, which advances PET imaging of γδ T cells and supports the translation of imaging agents for immunotherapeutic monitoring.
PURPOSE: γδ T cell-based immunotherapy has been rolled out as a promising treatment strategy for malignant tumors due to their potent anti-tumor cytotoxicity, ease of expansion, and unrestricted MHC feature. However, the dynamics and outcomes of γδ T cells in tumor sites are poorly understood. Reported strategies rely on ex vivo biolabeling, significantly limiting the application of γδ T cell molecular imaging. Herein, we investigated whether VLA-4 (very late antigen-4), a crucial component in the effective trafficking of lymphocytes, could serve as a biomarker to non-invasively visualize γδ T cells. METHODS: VLA-4-targeted tracer, 68 Ga-LLP2A, was evaluated in MDA-MB-231- and A549-bearing mice with adoptive transfer of γδ T cells by longitudinal PET/CT imaging. Imaging data were verified by ex vivo biodistribution studies, and the co-localization of CD3 and VLA-4 was validated by immunohistochemistry studies. RESULTS: 68 Ga-LLP2A showed high specificity to VLA-4-expressing γδ T cells in both in vitro and tumor-bearing mice with adoptive transfer of γδ T cells. Longitudinal PET imaging of 68 Ga-LLP2A in tumor-bearing mice with adoptive transfer of γδ T cells showed an increasing tumor tracer uptake, revealing the tumor-specific homing of γδ T cells. The presence of VLA-4-expressing γδ T cells in tumors was confirmed via histological analysis. CONCLUSION: To the best of our knowledge, we reported the first molecular probe, 68 Ga-LLP2A, for in vivo imaging of γδ T cells in live tumors, which advances PET imaging of γδ T cells and supports the translation of imaging agents for immunotherapeutic monitoring.
Authors: Andrew J Gentles; Aaron M Newman; Chih Long Liu; Scott V Bratman; Weiguo Feng; Dongkyoon Kim; Viswam S Nair; Yue Xu; Amanda Khuong; Chuong D Hoang; Maximilian Diehn; Robert B West; Sylvia K Plevritis; Ash A Alizadeh Journal: Nat Med Date: 2015-07-20 Impact factor: 53.440
Authors: C T Morita; E M Beckman; J F Bukowski; Y Tanaka; H Band; B R Bloom; D E Golan; M B Brenner Journal: Immunity Date: 1995-10 Impact factor: 31.745