Myxoma virus (MyxV) is a rabbit-specific poxvirus. However, its ability to selectively target tumor cells has established it as a safe and effective anticancer therapy. To strengthen its preclinical efficacy, transgenes that can prolong cancer cell infection and enhance anti-tumor effector functions are currently being investigated. We engineered MyxV armed with CD47, to turn on a ‘do not eat me’ signal within infected cells with actively replicating viruses, and with IFN-γ to further activate host immune anticancer responses. Tumor suppressive activities were significantly enhanced by the dual-armed MyxV_CD47/IFN-γ compared to parental MyxV or single-armed MyxV_CD47 or MyxV_IFN-γ. In addition, significant increases in IFN-γ+ CD8+T-cells and CD4+ T-cells populations within tumor-infiltrating lymphocytes (TIL) were observed after MyxV_CD47/IFN-γ treatment. Notably, all groups treated with MyxV showed a marked reduction in Foxp3+ CD4+ regulatory T-cells (Tregs) within TIL. We also show that MyxV infection induces PD-L1 up-regulation in cancer cells, and combinational treatment of MyxV with anti-mouse PD-L1 antibodies (αPD-L1) further controlled tumor burden and increased survival in the syngeneic melanoma model B16F10. Our data demonstrate that a CD47 and IFNγ dual-armed MyxV is an effective oncolytic viral immunotherapeutic. These findings strongly support further preclinical investigations to develop next-generation MyxV-based immunotherapy approaches.
黏液瘤病毒（MyxV）是一种兔特异性痘病毒。然而，其选择性靶向肿瘤细胞的能力使其成为一种安全有效的抗癌疗法。为增强其临床前疗效，目前正在研究能够延长癌细胞感染并增强抗肿瘤效应功能的转基因。我们设计了携带CD47的MyxV，以在病毒活跃复制的感染细胞内启动“勿食我”信号，并同时携带IFN-γ以进一步激活宿主免疫抗癌反应。与亲本MyxV或单基因修饰的MyxV_CD47、MyxV_IFN-γ相比，双基因修饰的MyxV_CD47/IFN-γ显著增强了肿瘤抑制活性。此外，经MyxV_CD47/IFN-γ治疗后，肿瘤浸润淋巴细胞（TIL）中IFN-γ+ CD8+ T细胞和CD4+ T细胞群显著增加。值得注意的是，所有MyxV治疗组均显示TIL中Foxp3+ CD4+调节性T细胞（Tregs）明显减少。我们还发现MyxV感染可诱导癌细胞中PD-L1表达上调，而在同源黑色素瘤模型B16F10中，MyxV与抗小鼠PD-L1抗体（αPD-L1）的联合治疗进一步控制了肿瘤负荷并提高了生存率。我们的数据表明，CD47和IFNγ双基因修饰的MyxV是一种有效的溶瘤病毒免疫治疗剂。这些发现为开发基于MyxV的下一代免疫疗法提供了强有力的临床前研究依据。
肿瘤(癌症)患者之家