Department of Biomedical Engineering, University of California, Davis, Davis, California.
Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Clin Cancer Res. 2018 Oct 15;24(20):4976-4987. doi: 10.1158/1078-0432.CCR-18-0261. Epub 2018 Jul 2.
Noninvasive and quantitative tracking of CD8 T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Radiolabeling of an anti-CD8 cys-diabody (169cDb) with Cu was developed. The accumulation of Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains ( = 8/group studied with imaging and IHC or flow cytometry) after intravenous administration. Tumor-infiltrating CD8 T cells in tumor-bearing mice treated with CpG and αPD-1 were quantified and mapped ( = 6-8/group studied with imaging and IHC or flow cytometry). We demonstrate the ability of immunoPET to detect small differences in CD8 T-cell distribution between mouse strains and across lymphoid tissues, including the intestinal tract of normal mice. In FVB mice bearing a syngeneic -driven model of mammary adenocarcinoma (NDL), Cu-169cDb PET imaging accurately visualized and quantified changes in tumor-infiltrating CD8 T cells in response to immunotherapy. A reduction in the circulation time of the imaging probe followed the development of treatment-related liver and splenic hypertrophy and provided an indication of off-target effects associated with immunotherapy protocols. Cu-169cDb imaging can spatially map the distribution of CD8 T cells in normal organs and tumors. ImmunoPET imaging of tumor-infiltrating cytotoxic CD8 T cells detected changes in T-cell density resulting from adjuvant and checkpoint immunotherapy protocols in our preclinical evaluation. .
通过 PET 进行非侵入性和定量追踪 CD8 T 细胞已成为评估免疫疗法反应的潜在技术。我们应用一种标记有 Cu 的抗 CD8 cys-二抗体来评估正常和患病组织的 PET 成像的灵敏度。开发了一种抗 CD8 cys-二抗体（169cDb）与 Cu 的放射性标记。在静脉给药后，通过 PET/CT 成像（0、5 和 24 小时）和生物分布（24 小时）评估 Cu-169cDb 的积累，在野生型小鼠品系（= 8/组，用 IHC 或流式细胞术进行成像和研究）中。用 CpG 和 αPD-1 处理荷瘤小鼠的肿瘤浸润 CD8 T 细胞进行了定量和定位（= 6-8/组，用成像和 IHC 或流式细胞术进行研究）。我们证明了 immunoPET 能够检测到不同小鼠品系和不同淋巴组织（包括正常小鼠的肠道）之间 CD8 T 细胞分布的微小差异。在携带同源驱动的乳腺腺癌（NDL）模型的 FVB 小鼠中，Cu-169cDb PET 成像能够准确地可视化和定量免疫治疗后肿瘤浸润 CD8 T 细胞的变化。成像探针循环时间的缩短与治疗相关的肝脾肿大的发展有关，并提示与免疫治疗方案相关的脱靶效应。Cu-169cDb 成像可以空间定位正常器官和肿瘤中 CD8 T 细胞的分布。肿瘤浸润细胞毒性 CD8 T 细胞的 immunoPET 成像检测到我们在临床前评估中辅助和检查点免疫治疗方案引起的 T 细胞密度变化。
