Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Molecular Imaging, Wuhan 430022, China.
National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, College of Bioengineering, Hubei University of Technology, Wuhan 430068, China.
Biomed Pharmacother. 2024 Sep;178:117060. doi: 10.1016/j.biopha.2024.117060. Epub 2024 Jul 24.
Due to the size and location of the tumor, incomplete radiofrequency ablation (iRFA) of the target tumor inhibits tumor immunity. In this study, a murine herpes simplex virus (oHSV2-mGM) armed with granulocyte-macrophage colony-stimulating factor (GM-CSF) was constructed to explore its effect on innate and adaptive immunity during iRFA, and the inhibitory effect of programmed cell death-1 (PD1) on tumor.
We verified the polarization and activation of RAW264.7 cells mediated by oHSV2-mGM in vitro. Subsequently, we evaluated the efficacy of oHSV2-mGM alone and in combination with αPD1 in the treatment of residual tumors after iRFA in two mouse models. RNA-seq was used to characterize the changes of tumor microenvironment.
oHSV2-mGM lysate effectively stimulated RAW264.7 cells to polarize into M1 cells and activated M1 phenotypic function. In the macrophage clearance experiment, oHSV2-mGM activated the immune response of tumor in mice. The results in vivo showed that oHSV2-mGM showed better anti-tumor effect in several mouse tumor models. Finally, oHSV2-mGM combined with PD1 antibody can further enhance the anti-tumor effect of oHSV2-mGM and improve the complete remission rate of tumor in mice.
The application of oHSV2-mGM leads to the profound remodeling of the immune microenvironment of residual tumors. oHSV2-mGM also works in synergy with PD1 antibody to achieve complete remission of tumors that do not respond well to monotherapy at immune checkpoints. Our results support the feasibility of recombinant oncolytic virus in the treatment of residual tumors after iRFA, and propose a new strategy for oncolytic virus treatment of tumors.
由于肿瘤的大小和位置，目标肿瘤的不完全射频消融（iRFA）会抑制肿瘤免疫。在这项研究中，构建了一种携带粒细胞-巨噬细胞集落刺激因子（GM-CSF）的小鼠单纯疱疹病毒（oHSV2-mGM），以探索其在 iRFA 期间对固有和适应性免疫的影响，以及程序性细胞死亡-1（PD1）对肿瘤的抑制作用。
我们在体外验证了 oHSV2-mGM 对 RAW264.7 细胞的极化和激活作用。随后，我们在两种小鼠模型中评估了 oHSV2-mGM 单独和联合 αPD1 在 iRFA 后残余肿瘤治疗中的疗效。使用 RNA-seq 来描述肿瘤微环境的变化。
oHSV2-mGM 裂解物有效地刺激 RAW264.7 细胞极化为 M1 细胞，并激活了 M1 表型功能。在巨噬细胞清除实验中，oHSV2-mGM 激活了小鼠肿瘤的免疫反应。体内结果表明，oHSV2-mGM 在几种小鼠肿瘤模型中表现出更好的抗肿瘤效果。最后，oHSV2-mGM 联合 PD1 抗体可以进一步增强 oHSV2-mGM 的抗肿瘤效果，并提高小鼠肿瘤的完全缓解率。
oHSV2-mGM 的应用导致残余肿瘤免疫微环境的深刻重塑。oHSV2-mGM 还与 PD1 抗体协同作用，实现了对免疫检查点单药治疗反应不佳的肿瘤的完全缓解。我们的结果支持了重组溶瘤病毒在 iRFA 后残余肿瘤治疗中的可行性，并为溶瘤病毒治疗肿瘤提出了一种新策略。
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