Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：由于肿瘤的大小和位置，靶肿瘤的不完全射频消融（iRFA）抑制肿瘤免疫。在这项研究中,构建了携带粒细胞-巨噬细胞集落刺激因子（GM-CSF）的小鼠单纯疱疹病毒（oHSV2-mGM），以探讨其在iRFA过程中对先天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。
方法：我们在体外验证了oHSV2-mGM介导的RAW264.7细胞的极化和激活。随后，我们在两种小鼠模型中评估了oHSV2-mGM单独和与αPD1联合治疗iRFA后残留肿瘤的疗效.RNA-seq用于表征肿瘤微环境的变化。
结果：oHSV2-mGM裂解物有效刺激RAW264.7细胞极化为M1细胞并激活M1表型功能。在巨噬细胞清除实验中,oHSV2-mGM激活小鼠肿瘤的免疫应答。体内实验结果表明，oHSV2-mGM在几种小鼠肿瘤模型中表现出更好的抗肿瘤作用。最后,oHSV2-mGM联合PD1抗体可进一步增强oHSV2-mGM的抗肿瘤作用,提高小鼠肿瘤的完全缓解率。
结论：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,以实现在免疫检查点对单一疗法反应不佳的肿瘤的完全缓解。我们的结果支持重组溶瘤病毒治疗iRFA后残留肿瘤的可行性，并提出溶瘤病毒治疗肿瘤的新策略。
方法：我们在体外验证了oHSV2-mGM介导的RAW264.7细胞的极化和激活。随后，我们在两种小鼠模型中评估了oHSV2-mGM单独和与αPD1联合治疗iRFA后残留肿瘤的疗效.RNA-seq用于表征肿瘤微环境的变化。
结果：oHSV2-mGM裂解物有效刺激RAW264.7细胞极化为M1细胞并激活M1表型功能。在巨噬细胞清除实验中,oHSV2-mGM激活小鼠肿瘤的免疫应答。体内实验结果表明，oHSV2-mGM在几种小鼠肿瘤模型中表现出更好的抗肿瘤作用。最后,oHSV2-mGM联合PD1抗体可进一步增强oHSV2-mGM的抗肿瘤作用,提高小鼠肿瘤的完全缓解率。
结论：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,以实现在免疫检查点对单一疗法反应不佳的肿瘤的完全缓解。我们的结果支持重组溶瘤病毒治疗iRFA后残留肿瘤的可行性，并提出溶瘤病毒治疗肿瘤的新策略。
