N-[C]甲基-AMD3465 PET 可无创监测肿瘤异种移植中 CXCR4 表达的治疗诱导变化。

Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[C]Methyl-AMD3465 PET.

机构信息

Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 31.001, 9713, GZ, Groningen, The Netherlands.

Department of Medical Microbiology, Tumor Virology and Cancer Immunotherapy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

出版信息

Mol Imaging Biol. 2020 Aug;22(4):883-890. doi: 10.1007/s11307-019-01447-x.

DOI:10.1007/s11307-019-01447-x

PMID:31802362

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7343732/

Abstract

PURPOSE

Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[C]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization.

PROCEDURE

TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[C]methyl-AMD3465 PET.

RESULTS

PET imaging showed N-[C]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 ± 0.31 %ID/g vs. 0.42 ± 0.05 % ID/g, p < 0.01). The tumor uptake was further increased by 4-fold (1.73 ± 0.17 % ID/g vs 0.42 ± 0.05 % ID/g, p < 0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 ± 0.1 % ID/g, p < 0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis.

CONCLUSION

This study demonstrates the feasibility of N-[C]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.

摘要

目的

趋化因子 CXCL12 和其受体 CXCR4 在人类癌症中持续过表达。CXCL12-CXCR4 信号轴在肿瘤进展和转移中发挥重要作用，但也在治疗诱导的表达 CXCR4 的细胞毒性免疫细胞募集中发挥作用。在这里，我们旨在证明 N-[C]甲基-AMD3465 正电子发射断层扫描（PET）监测单次局部放疗后或联合免疫治疗后肿瘤中 CXCR4 密度变化的可行性。

程序

将表达人乳头瘤病毒抗原 E6 和 E7 的 TC-1 细胞皮下接种到 C57BL/6 小鼠中。肿瘤细胞接种后 2 周，用单次 14Gy 剂量的 X 射线照射小鼠。一组照射后的小鼠用α病毒载体疫苗 SFVeE6,7 免疫，另一组每天腹腔注射 CXCR4 拮抗剂 AMD3100（3mg/kg）。照射后 7 天，所有动物均进行 N-[C]甲基-AMD3465 PET 检查。

结果

PET 成像显示，单次照射小鼠肿瘤的 N-[C]甲基-AMD3465 摄取量比假照射肿瘤高近 2.5 倍（1.07±0.31%ID/g 比 0.42±0.05%ID/g，p<0.01）。单次放疗联合 SFVeE6,7 免疫治疗可使肿瘤摄取量进一步增加 4 倍（1.73±0.17%ID/g 比 0.42±0.05%ID/g，p<0.01）。AMD3100 给药可使照射动物肿瘤中示踪剂摄取量减少 4.5 倍（0.24±0.1%ID/g，p<0.001），提示示踪剂摄取确实是由于 CXCR4 介导的趋化作用。