减毒麻疹病毒 (MV) 在缺乏 I 型干扰素 (IFN-I) 产生或反应性的恶性胸膜间皮瘤 (MPM) 细胞中发挥其溶瘤活性。然而，肿瘤微环境（TME）中的其他细胞，例如骨髓细胞，具有功能性抗病毒途径。在这项研究中，我们旨在表征人 MPM 中 MV 和骨髓细胞之间的相互作用。我们将 MPM 细胞系与单核细胞或巨噬细胞共培养，并用 MV 感染它们。我们分析了每种细胞类型的转录组，并通过高维流式细胞术研究了它们的分泌和表型。我们还使用 MV 编码 GFP (MV-GFP) 测量转基因表达。我们发现 MPM 细胞驱动单核细胞分化为 M2 样巨噬细胞。这些巨噬细胞抑制存在IFN-I产生缺陷和IFN-I受体下游功能信号传导缺陷的肿瘤细胞中的GFP表达，同时对具有对IFN-I反应性缺陷的肿瘤细胞中的GFP表达影响最小。有趣的是，鲁索替尼抑制 IFN-I 信号传导可恢复肿瘤细胞中的 GFP 表达。 MV 感染后，共培养的巨噬细胞表达抗病毒促炎基因，并诱导肿瘤细胞中 IFN 刺激基因的表达。 MV 还增加巨噬细胞上 HLA 和共刺激分子的表达及其吞噬活性。最后，MV诱导炎症细胞因子的分泌，尤其是IFN-I，以及肿瘤细胞和巨噬细胞中PD-L1的表达。这些结果表明，巨噬细胞通过产生 IFN-I 来减少某些 MPM 细胞系中病毒蛋白的表达，并产生促炎相互作用，可能会刺激患者的抗肿瘤免疫反应。© 2024 作者。经泰勒许可出版

Attenuated measles virus (MV) exerts its oncolytic activity in malignant pleural mesothelioma (MPM) cells that lack type-I interferon (IFN-I) production or responsiveness. However, other cells in the tumor microenvironment (TME), such as myeloid cells, possess functional antiviral pathways. In this study, we aimed to characterize the interplay between MV and the myeloid cells in human MPM. We cocultured MPM cell lines with monocytes or macrophages and infected them with MV. We analyzed the transcriptome of each cell type and studied their secretion and phenotypes by high-dimensional flow cytometry. We also measured transgene expression using an MV encoding GFP (MV-GFP). We show that MPM cells drive the differentiation of monocytes into M2-like macrophages. These macrophages inhibit GFP expression in tumor cells harboring a defect in IFN-I production and a functional signaling downstream of the IFN-I receptor, while having minimal effects on GFP expression in tumor cells with defect of responsiveness to IFN-I. Interestingly, inhibition of the IFN-I signaling by ruxolitinib restores GFP expression in tumor cells. Upon MV infection, cocultured macrophages express antiviral pro-inflammatory genes and induce the expression of IFN-stimulated genes in tumor cells. MV also increases the expression of HLA and costimulatory molecules on macrophages and their phagocytic activity. Finally, MV induces the secretion of inflammatory cytokines, especially IFN-I, and PD-L1 expression in tumor cells and macrophages. These results show that macrophages reduce viral proteins expression in some MPM cell lines through their IFN-I production and generate a pro-inflammatory interplay that may stimulate the patient's anti-tumor immune response.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.