溶瘤性麻疹病毒，巨噬细胞和癌细胞之间的相互作用诱导促炎性肿瘤微环境
Interplay between oncolytic measles virus, macrophages and cancer cells induces a proinflammatory tumor microenvironment
影响因子:6.30000
分区:医学2区 / 免疫学2区 肿瘤学2区
发表日期:2024
作者:
Camille Chatelain, Laurine Berland, Marion Grard, Nicolas Jouand, Judith Fresquet, Joëlle Nader, Ugo Hirigoyen, Tacien Petithomme, Chantal Combredet, Elvire Pons-Tostivint, Delphine Fradin, Lucas Treps, Christophe Blanquart, Nicolas Boisgerault, Frédéric Tangy, Jean-François Fonteneau
摘要
减弱的麻疹病毒（MV）在缺乏I型Intyferon（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。但是，肿瘤微环境（TME）中的其他细胞（例如髓样细胞）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和髓样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结合，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仪研究了它们的分泌和表型。我们还使用MV编码GFP（MV-GFP）测量了转基因表达。我们表明，MPM细胞将单核细胞的分化驱动为M2样巨噬细胞。这些巨噬细胞抑制IFN-I产生缺陷和IFN-I受体下游的功能信号的肿瘤细胞中的GFP表达，同时对肿瘤细胞中GFP表达的影响最小，并且对IFN-I的反应性缺陷。有趣的是，违反违反IFN-I信号的抑制会恢复肿瘤细胞中的GFP表达。 MV感染后，共培养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还增加了HLA和共刺激分子在巨噬细胞及其吞噬活性上的表达。最后，MV诱导炎症细胞因子的分泌，尤其是IFN-I，以及在肿瘤细胞和巨噬细胞中的PD-L1表达。这些结果表明，巨噬细胞通过其IFN-I产生降低了一些MPM细胞系中病毒蛋白的表达，并产生促炎性相互作用，可能会刺激患者的抗肿瘤免疫反应。
Abstract
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.