肿瘤溶解性麻疹病毒、巨噬细胞与癌细胞相互作用引发促炎肿瘤微环境

Interplay between oncolytic measles virus, macrophages and cancer cells induces a proinflammatory tumor microenvironment

OncoImmunology

影响因子:6.3

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

DOI: 10.1080/2162402X.2024.2377830

摘要

减毒麻疹病毒（MV）在缺乏I型干扰素（IFN-I）产生或反应的恶性胸膜间皮瘤（MPM）细胞中表现出其溶瘤活性。然而，肿瘤微环境（TME）中的其他细胞，如髓系细胞，具有功能性抗病毒途径。在本研究中，我们旨在描述MV与人类MPM中髓系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，分析每种细胞类型的转录组，研究其分泌物和表型，通过高维流式细胞术进行分析。我们还利用编码GFP的MV（MV-GFP）测定转基因表达。结果显示，MPM细胞驱动单核细胞向M2样巨噬细胞分化，这些巨噬细胞抑制携带IFN-I缺陷和具有IFN-I受体下游信号通路正常的肿瘤细胞中的GFP表达，而对响应IFN-I缺陷的肿瘤细胞影响较小。有趣的是，利用ruxolitinib抑制IFN-I信号可以恢复肿瘤细胞中的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还增加巨噬细胞表面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，特别是IFN-I和PD-L1在肿瘤细胞及巨噬细胞中的表达。这些结果表明，巨噬细胞通过其IFN-I产生减少某些MPM细胞系中的病毒蛋白表达，并产生促进炎症的相互作用，可能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.