作者投稿
专家审稿
编辑办公
邮件订阅
RSS
Integrin αvβ3 Targeted Radiopharmaceutical 99mTc-RGD Combined with Anti-PD-L1 mAb to Enhance the Anti-tumor Effect in Tumor Immunotherapy
-
摘要:
目的 探讨诊断类放射性核素99mTc标记的多肽精氨酰-甘氨酰-天冬氨酸(RGD)对肿瘤免疫微环境的调控作用以及联合抗程序性死亡受体配体1(programmed death-ligand 1，PD-L1)抗体增强抗肿瘤治疗的效果。 方法 采用流式细胞术对肿瘤细胞的PD-L1表达水平进行检测，采用单光子发射计算机断层显像(single photon emission computed tomography，SPECT)评估99mTc-RGD在MC38肿瘤鼠中的分布情况，采用99mTc-RGD联合抗PD-L1抗体对MC38肿瘤鼠模型进行治疗，评价其抗肿瘤治疗效果。 结果 经99mTc-RGD诱导后，CT26、MC38、4T1和B16F10肿瘤细胞表面的PD-L1表达水平均显著上调，差异具有显著统计学意义(P均＜0.01); 以MC38肿瘤鼠为模型，对其注射99mTc-RGD并进行SPECT显像，结果显示存在明显的肿瘤摄取; 99mTc-RGD联合抗PD-L1抗体治疗MC38肿瘤鼠模型的研究结果表明，不同的给药剂量和时间窗可对联合治疗效果产生显著影响，18.5 MBq或37 MBq 99mTc-RGD联合抗PD-L1抗体在间隔4 h时间窗时产生最佳治疗效果。 结论 99mTc-RGD可诱导肿瘤细胞表面PD-L1表达水平上调，联合抗PD-L1抗体可增强抗肿瘤治疗效果。 Abstract:Objective To investigate the effect of 99mTc-labeled RGD peptide (99mTc-RGD) on regulating the tumor immune microenvironment and enhancing the anti-tumor effect of immunotherapy when combined with anti-programmed death-ligand 1 (PD-L1) antibody. Methods The expression of PD-L1 on tumor cells was detected by flow cytometry, and the distribution of 99mTc-RGD in MC38 tumor mice was evaluated using single photon emission computed tomography(SPECT) imaging. The combination therapy was performed to monitor the anti-tumor effect. Results The expression of PD-L1 on CT26, MC38, 4T1 and B16F10 tumor cells was upregulated after being induced by 99mTc-RGD, and there was a statistical significance between 99mTc-RGD treated and untreated groups. Subsequently, SPECT imaging was performed by injecting 99mTc-RGD into MC38 tumor-bearing mice, and significant tumor uptake was observed. Based on this, the combination of 99mTc-RGD and anti-PD-L1 antibody in MC38 tumor mice was studied, and the results showed that different doses and time windows had significant effects on the efficacy of the combination therapy. The combination of 18.5 MBq or 37 MBq 99mTc-RGD with an anti-PD-L1 antibody led to the best therapeutic effect at 4 h intervals. Conclusions 99mTc-RGD could induce the upregulation of tumor PD-L1 expression, and when combined with an anti-PD-L1 antibody, it could enhance the anti-tumor effect. -
Key words:
- radiopharmaceuticals /
- PD-L1 /
- tumor immunotherapy /
- tumor models
作者贡献：文雪君负责实验设计、实验操作、数据处理、文献查阅及论文初稿撰写；周吴昊负责文献查阅和资料收集；郭志德、张现忠负责选题设计，并指导论文修订。利益冲突：所有作者均声明不存在利益冲突 -
图 1 流式细胞术评估肿瘤细胞表面PD-L1表达水平变化
A.99mTc-RGD诱导后4种肿瘤细胞在不同时间窗的PD-L1表达水平上调情况；B. 99mTc-RGD诱导后4种肿瘤细胞在不同时间窗的PD-L1表达水平定量结果(*P＜0.01，**P＜0.001)
图 3 99mTc-RGD联合αPD-L1改善MC38肿瘤鼠模型的治疗效果
A. 99mTc-RGD联合αPD-L1抗体治疗MC38肿瘤鼠模型的程序和时间窗示意图(当肿瘤体积达到50 mm3左右时开始治疗，小鼠被随机分为13组，每组8只，治疗第4天行第二疗程给药)；B.不同治疗组MC38肿瘤鼠模型90 d内单只小鼠的肿瘤生长曲线
#区分不同的给药剂量；99mTc-R: 99mTc-RGD; αP: αPD-L1抗体；@4 h(24 h): 间隔4 h(24 h)时间窗 -
[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. Ca Cancer J Clin, 2021, 71: 209-249. doi: 10.3322/caac.21660 [2] Das S, Al-Toubah T, El-Haddad G, et al. Lu-177-DOTA-TATE for the treatment of gastroenteropancreatic neuroendocrine tumors[J]. Expert Rev Gastroent, 2019, 13: 1023-1031. doi: 10.1080/17474124.2019.1685381 [3] Hennrich U, Eder M. [Lu-177] Lu-PSMA-617 (Pluvicto (TM)): The First FDA-Approved Radiotherapeutical for Treatment of Prostate Cancer[J]. Pharmaceuticals, 2022, 15: 1292. doi: 10.3390/ph15101292 [4] Wen XJ, Zeng XY, Shing CR, et al. PD-L1-Targeted Radionuclide Therapy Combined with alpha PD-L1 Antibody Immunotherapy Synergistically Improves the Antitumor Effect[J]. Mol Pharmaceut, 2022, 19: 3612-3622. doi: 10.1021/acs.molpharmaceut.2c00281 [5] Wen XJ, Zeng XY, Shi CR, et al. Optimum Combination of Radiopharmaceuticals-Based Targeting-Triggering-Therapy Effect and PD-L1 Blockade Immunotherapy[J]. Adv Therap, 2023, 6: 22001 [6] Gutfilen B, Al Souza S, Valentini G. Copper-64: a real theranostic agent[J]. Drug Des Dev Ther, 2018, 12: 3235-3245. doi: 10.2147/DDDT.S170879 [7] Wen XJ, Zeng XY, Liu J, et al. Synergism of Cu-64-Labeled RGD with Anti-PD-L1 Immunotherapy for the Long-Acting Antitumor Effect[J]. Bioconjugate Chem, 2022, 33: 2170-2179. doi: 10.1021/acs.bioconjchem.2c00408 [8] Wen XJ, Shi CR, Zeng XY, et al. A Paradigm of Cancer Immunotherapy Based on 2-[18F] FDG and Anti-PD-L1 mAb Combination to Enhance the Antitumor Effect[J]. Clin Cancer Res, 2022, 28: 2923-2937. doi: 10.1158/1078-0432.CCR-22-0159 [9] Niu G, Chen XY. Why Integrin as a Primary Target for Imaging and Therapy[J]. Theranostics, 2011, 1: 30-47. doi: 10.7150/thno/v01p0030 [10] Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis[J]. Nat Rev Cancer, 2018, 18: 532-547. [11] Zhou Y, Kim YS, Chakraborty S, et al. 99mTc-Labeled Cyclic RGD Peptides for Noninvasive Monitoring of Tumor Integrin αvβ3 Expression[J]. Mol Imaging, 2011, 10: 386-397. [12] Zhou Y, Kim YS, Lu X, et al. Evaluation of 99mTc-labeled cyclic RGD dimers: impact of cyclic RGD peptides and 99mTc chelates on biological properties[J]. Bioconjug Chem, 2012, 23: 586-595. doi: 10.1021/bc200631g [13] Baskar R, Lee K A, Yeo R, et al. Cancer and Radiation Therapy: Current Advances and Future Directions[J]. Int J Med Sci, 2012, 9: 193-199. doi: 10.7150/ijms.3635 [14] Norouzi S, Gorgi Valokala M, Mosaffa F, et al. Crosstalk in cancer resistance and metastasis[J]. Crit Rev Oncol Hematol, 2018, 132: 145-153. doi: 10.1016/j.critrevonc.2018.09.017 [15] Kornepati AVR, Vadlamudi RK, Curiel TJ. Programmed death ligand 1 signals in cancer cells[J]. Nat Rev Cancer, 2022, 22: 190. doi: 10.1038/s41568-022-00445-6 [16] Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy[J]. Science, 2020, 367: eaax0182. doi: 10.1126/science.aax0182 [17] de Miguel M, Calvo E. Clinical Challenges of Immune Checkpoint Inhibitors[J]. Cancer Cell, 2020, 38: 326-333. doi: 10.1016/j.ccell.2020.07.004 -
下载:
点击查看大图
图(4)
计量
- 文章访问数: 1597
- HTML全文浏览量: 41
- PDF下载量: 57
- 被引次数: 0
