肿瘤细胞治疗研究
英文原题：In Vivo PET Imaging of (89)Zr-Labeled Natural Killer Cells and the Modulating Effects of a Therapeutic Antibody.
本研究证明了使用 PET 对 89 Zr-NK 细胞浸润实体瘤进行成像的可行性。
自然杀伤（NK）细胞可通过抗体依赖性细胞介导的细胞毒作用（ADCC）杀伤癌细胞：肿瘤相关 IgG 抗体通过其 Fc 区与 NK 细胞 Fc 受体 CD16 结合，从而激活 NK 细胞的细胞毒功能。本研究采用 PET 成像评估 NK 细胞向人表皮生长因子受体 2（HER2）阳性 HCC1954 乳腺肿瘤的迁移，并考察靶向 HER2 的曲妥珠单抗治疗对 NK 细胞肿瘤蓄积的影响。方法：体外扩增健康供者的人 NK 细胞，并以 [89Zr]Zr-oxine 标记。体外实验比较标记（89Zr-NK）和未标记 NK 细胞的表型标志物、存活、增殖、迁移、脱颗粒及 ADCC 功能。携带原位人乳腺 HCC1954 肿瘤的雌性小鼠接受 89Zr-NK 细胞，同时给予曲妥珠单抗或假处理，并在 7 天内进行 PET/CT 扫描。通过流式细胞术和 γ 计数分析肝脏及脾脏组织中 89Zr-NK 细胞的分布。结果：89Zr 细胞放射性标记产率为 42.2%±8.0%。在平均比活度为每 10^6 个细胞 16.7±4.7 kBq 时，89Zr-NK 细胞保留了包括 CD56 和 CD16 表达、存活、迁移、脱颗粒及 ADCC 能力在内的表型和功能特征。体内 PET/CT 显示 89Zr-NK 细胞主要蓄积于肝脏和脾脏。肝脏及脾脏组织离体分析表明，输注的人 89Zr-NK 细胞在体内保留放射性，89Zr 也未转移至小鼠软组织细胞，由此验证了使用 89Zr PET 追踪 NK 细胞的方法。值得注意的是，无论是否接受曲妥珠单抗治疗，89Zr-NK 细胞均可迁移至 HER2 阳性肿瘤。曲妥珠单抗治疗与注射后第 1 天和第 3 天 89Zr-NK 细胞信号增强相关。结论：体外实验中，89Zr-NK 细胞保持了关键细胞功能和细胞毒功能；体内实验中，89Zr-NK 细胞可迁移至 HER2 阳性肿瘤，且曲妥珠单抗治疗与 89Zr-NK 浸润增加相关。本研究证明了采用 PET 成像观察 89Zr-NK 细胞浸润实体瘤的可行性。
Natural killer (NK) cells can kill cancer cells via antibody-dependent cell-mediated cytotoxicity (ADCC): a tumor-associated IgG antibody binds to the Fc receptor CD16 on NK cells via the antibody Fc region and activates the cytotoxic functions of the NK cell. Here, we used PET imaging to assess NK cell migration to human epidermal growth factor receptor 2 (HER2)-positive HCC1954 breast tumors, examining the influence of HER2-targeted trastuzumab antibody treatment on NK cell tumor accumulation. Methods: Human NK cells from healthy donors were expanded ex vivo and labeled with [ 89 Zr]Zr-oxine. In vitro experiments compared the phenotypic markers, viability, proliferation, migration, degranulation, and ADCC behaviors of both labeled ( 89 Zr-NK) and unlabeled NK cells. Female mice bearing orthotopic human breast HCC1954 tumors were administered 89 Zr-NK cells alongside trastuzumab treatment or a sham treatment and then scanned using PET/CT imaging over 7 d. Flow cytometry and -counting were used to analyze the presence of 89 Zr-NK cells in liver and spleen tissues. Results: 89 Zr cell radiolabeling yields measured 42.2% 8.0%. At an average specific activity of 16.7 4.7 kBq/10 6 cells, 89 Zr-NK cells retained phenotypic and functional characteristics including CD56 and CD16 expression, viability, migration, degranulation, and ADCC capabilities. In vivo PET/CT studies indicated predominant accumulation of 89 Zr-NK cells in the liver and spleen. Ex vivo analyses of liver and spleen tissues indicated that the administered human 89 Zr-NK cells retained their radioactivity in vivo and that 89 Zr did not transfer to cells of murine soft tissues, thus validating this 89 Zr PET method for NK cell tracking. Notably, 89 Zr-NK cells migrated to HER2-positive tumors, both with and without trastuzumab treatment. Trastuzumab treatment was associated with an increased 89 Zr-NK cell signal at days 1 and 3 after injection. Conclusion: In vitro, 89 Zr-NK cells maintained key cellular and cytotoxic functions. In vivo, 89 Zr-NK cells trafficked to HER2-postive tumors, with trastuzumab treatment correlating with enhanced 89 Zr-NK infiltration. This study demonstrates the feasibility of using PET to image 89 Zr-NK cell infiltration into solid tumors.
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