期刊
CANCER LETTERS
卷 502, 期 -, 页码 9-24出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.12.018
关键词
Irreversible electroporation; Oncolytic-virotherapy; Immune activation; Reactive oxygen species; Apoptosis
类别
资金
- National Natural Science Funds of China [81972299, 81672390]
- National Key Research and Development Plan of China [2017YFC0910002]
- Pioneering talents project of Guangzhou Development Zone, Guangdong Province [CY2018-012]
- National Major Scientific and Technological Special Project for Significant New Drug Development [2018ZX09733002]
- Leading Team for Entrepreneurship in Guangzhou, Guangdong Province [201809020004]
NanoKnife, a nonthermal ablation technique, combined with M1 virus shows synergistic therapeutic efficacy in treating locally advanced pancreatic cancer, enhancing tumor inhibition and prolonging survival in immunocompetent mice. The combination promotes M1 infection, converting immune-silent tumors into immune-inflamed tumors and potentially improving prognosis for LAPC patients.
NanoKnife, a nonthermal ablation technique also termed irreversible electroporation (IRE), has been adopted in locally advanced pancreatic cancer (LAPC) treatment. However, reversible electroporation (RE) caused by heterogeneous electric field magnitude leads to inadequate ablation and tumor recurrence. Alphavirus M1 has been identified as a novel natural oncolytic virus which is nonpathogenic and with high tumor selectivity. This study evaluated improvements to therapeutic efficacy through combination therapy incorporating NanoKnife and M1 virus. We showed that IRE triggered reactive oxygen species (ROS)-dependent apoptosis in pancreatic cancer cells (PCCs) mediated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. When NanoKnife was combined with M1 virus, the therapeutic efficacy was synergistically enhanced. The combinatorial treatment further inhibited tumor proliferation and prolonged the survival of orthotopic pancreatic cancer (PC)-bearing immunocompetent mice. In depth, NanoKnife enhanced the oncolytic effect of M1 by promoting its infection. The combination turned immune-silent tumors into immune-inflamed tumors characterized by T cell activation. Clinicopathologic analysis of specific M1 oncolytic biomarkers indicated the potential of the combination regimen. The combinatorial therapy represents a promising therapeutic efficacy and may ultimately improve the prognosis of patients with LAPC.
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