- 作者: Da-Liang Ou, Zi-Xian Liao, Ivan M. Kempson, Lin Li, Pan-Chyr Yang & S.-Ja Tseng
- 作者服務機構: 1.Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, 10051, Taiwan 2.Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia 3.Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan 4.Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan 5.Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan 6.National Taiwan University YongLin Institute of Health, National Taiwan University, Taipei, 10051, Taiwan 7.Program in Precision Health and Intelligent Medicine, Graduate School of Advanced Technology, National Taiwan University, Taipei, 10051, Taiwan
- 中文摘要:
- 英文摘要:
Background
As of 2020, hepatocellular carcinoma (HCC), a form of liver cancer, stood as the third most prominent contributor to global cancer-related mortality. Combining immune checkpoint inhibitors (ICI) with other therapies has shown promising results for treating unresectable HCC, offering new opportunities. Recombinant adeno-associated viral type 2 (AAV2) virotherapy has been approved for clinical use but it efficacy is stifled through systemic administration. On the other hand, iron oxide nanoparticles (ION) can be cleared via the liver and enhance macrophage polarization, promoting infiltration of CD8+ T cells and creating a more favorable tumor microenvironment for immunotherapy.
Methods
To enhance the efficacy of virotherapy and promote macrophage polarization towards the M1-type in the liver, ION-AAV2 were prepared through the coupling of ION-carboxyl and AAV2-amine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)/N-hydroxysulfosuccinimide (Sulfo-NHS). Efficacy after systemic delivery of ION-AAV2 in an orthotopic HCC model was evaluated.
Results
After 28 days, the tumor weight in mice treated with ION-AAV2 was significantly reduced by 0.56-fold compared to the control group. The ION-AAV2 treatment led to an approximate 1.80-fold increase in the level of tumor associated M1-type macrophages, while the number of M2-type macrophages was reduced by 0.88-fold. Moreover, a proinflammatory response increased the population of tumor-infiltrating CD8+ T cells in the ION-AAV2 group. This transformation converted cold tumors into hot tumors.
Conclusions
Our findings suggest that the conjugation of ION with AAV2 could be utilized in virotherapy while simultaneously exploiting macrophage-modulating cancer immunotherapies to effectively suppress HCC growth. - 中文關鍵字:
- 英文關鍵字: Orthotopic hepatocellular carcinoma, Iron oxide nanoparticles, Adeno-associated virus, Immunepromoting efect, Macrophage, Photodynamic virotherapy