PDF(Pubmed)
Abstract：
UNASSIGNED: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness.
UNASSIGNED: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy\'s antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others.
UNASSIGNED: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment.
UNASSIGNED: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
UNASSIGNED: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy\'s antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others.
UNASSIGNED: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment.
UNASSIGNED: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
摘要：
■恶性周围神经鞘瘤（MPNST）由于手术切除后的高复发率和对传统化疗的无效反应而提出了重大的治疗挑战。另一种治疗策略是溶瘤病毒免疫疗法，它可以引发持久和系统性的抗肿瘤免疫反应，并被食品和药物管理局（FDA）批准用于治疗黑色素瘤。不幸的是,只有一部分患者完全有反应，强调需要解决阻碍病毒免疫疗法有效性的障碍。
在这里，我们研究了靶向MPNST免疫抑制微环境的关键成分以增强病毒免疫疗法在三种小鼠模型中的抗肿瘤功效的治疗效用，其中一个显示出比其他更多的免疫原性特征。
■用帕西达替尼进行骨髓调节治疗，CSF1R酪氨酸激酶的小分子抑制剂，在高免疫原性模型中，溶瘤性单纯疱疹病毒T-VEC的中位生存时间增加最显著。此外,用骨髓调节疗法靶向骨髓细胞，caspase-8依赖性凋亡的小分子激活剂，在免疫原性较低的MPNST模型中增加了T-VEC的生存益处。然而,未观察到肿瘤消退或缩小.耗竭实验证实,增强的存活益处依赖于T细胞应答。此外，联合病毒免疫疗法后的流式细胞术分析显示,肿瘤微环境中M2巨噬细胞和髓源性抑制细胞减少,肿瘤特异性gp70+CD8T细胞增加.
■总之，我们的研究结果为利用针对MPNST的骨髓细胞靶向的病毒免疫疗法的潜力提供了令人信服的证据,值得进一步研究.
在这里，我们研究了靶向MPNST免疫抑制微环境的关键成分以增强病毒免疫疗法在三种小鼠模型中的抗肿瘤功效的治疗效用，其中一个显示出比其他更多的免疫原性特征。
■用帕西达替尼进行骨髓调节治疗，CSF1R酪氨酸激酶的小分子抑制剂，在高免疫原性模型中，溶瘤性单纯疱疹病毒T-VEC的中位生存时间增加最显著。此外,用骨髓调节疗法靶向骨髓细胞，caspase-8依赖性凋亡的小分子激活剂，在免疫原性较低的MPNST模型中增加了T-VEC的生存益处。然而,未观察到肿瘤消退或缩小.耗竭实验证实,增强的存活益处依赖于T细胞应答。此外，联合病毒免疫疗法后的流式细胞术分析显示,肿瘤微环境中M2巨噬细胞和髓源性抑制细胞减少,肿瘤特异性gp70+CD8T细胞增加.
■总之，我们的研究结果为利用针对MPNST的骨髓细胞靶向的病毒免疫疗法的潜力提供了令人信服的证据,值得进一步研究.
