Synergism of 64Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect
Synergism of 64Cu-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect
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64Cu 标记的 RGD 与抗 PD-L1 免疫疗法协同发挥长效抗肿瘤作用
DOI：
10.1021/acs.bioconjchem.2c00408
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发表时间：
2022-10-18
影响因子：
4.7
通讯作者：
Guo，Zhide
中科院分区：
文献类型：
--
作者：
Wen，Xuejun;Zeng，Xinying;Guo，Zhide
我们提出了一种新的靶向触发治疗(TTT)方案，将64Cu基的靶向核素治疗(TRT)与基于程序性死亡配体1(PD-L1)的免疫治疗相结合，以提高疗效。合成了以整合素为靶标的αvβ3整合素64Cu-DOTA-EB-cRGDfK(64Cu-DER)。采用流式细胞术、免疫荧光染色和RT-qPCR法检测64CuDER照射后PD-L1表达的变化。用正电子发射断层扫描技术研究了64CuDER显著的肿瘤滞留特性。在MC38肿瘤模型中，注射64CuDER后同时或连续注射抗PD-L1抗体(αPD-L1mAb)，然后检测肿瘤微环境的变化。经64铜-DER诱导后，PD-L1呈时间和剂量依赖性上调。联合应用64Cu-der TRT(925MBq/kg)和αPD-L1单抗(10 mg/kg)可显著延缓肿瘤生长并保护肿瘤免受再攻击。64CuDER+αPD-L1mAb+64CuDER TRT后4h阻断PD-L1能达到100%的存活率，防止肿瘤复发，明显延长小鼠的生存时间。综上所述，64Cu-DER和αPD-L1单抗以时间依赖的方式结合可能是提高治疗效果的一种有前途的方法。可以理解的是，这一策略有可能扩大64Cu基TTT的范围，值得转化为临床实践，以更好地管理免疫检查点阻断免疫疗法。
We put forward a novel targeting-triggering-therapy (TTT) scheme that combines64Cu-based targeted radionuclide therapy (TRT) with programmed death-ligand 1 (PD-L1)-based immunotherapy for enhancing therapeutic efficacy. The αvβ3integrin-targeted64Cu-DOTA-EB-cRGDfK (64Cu-DER) was synthesized. Flow cytometry, immunofluorescence staining, and RT-qPCR were performed to verify PD-L1 upregulation after irradiation with64Cu-DER. Positron emission tomography imaging was performed to investigate the prominent tumor retention property of64Cu-DER. In the MC38 tumor model, anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner after64Cu-DER was injected, followed by the testing of changes in tumor microenvironment (TME). PD-L1 was upregulated in a time- and dose-dependent manner after being induced by64Cu-DER. The combination of64Cu-DER TRT (925 MBq/kg) and αPD-L1 mAb (10 mg/kg) resulted in significant delay in tumor growth and protected against tumor rechallenge. Blockade of PD-L1 at 4 h after64Cu-DER TRT (64Cu-DER + αPD-L1 mAb @ 4 h combination group) was able to achieve 100% survival rate, prevent tumor relapse, and evidently prolong the survival of mice. In summary, the combination of64Cu-DER and αPD-L1 mAb in a time-dependent manner could be a promising approach to improve therapeutic efficacy. Understandably, this strategy has the potential to extend the scope of64Cu-based TTT and merits translation into clinical practice for the better management of immune checkpoint blockade immunotherapy.