Hoyos Clotilde, Fontaine Alexis, Jacques Jean-Rock, Heinen Vincent, Louis Renaud, Duysinx Bernard, Scherpereel Arnaud, Wasielewski Eric, Jamakhani Majeed, Hamaidia Malik, Willems Luc
Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) and Molecular Biology, Teaching and Research Centre (TERRA), University of Liège, 4000 Liege, Belgium.
Department of Pneumology-Allergology, University Hospital, Sart-Tilman, 4000 Liege, Belgium.
Cancers (Basel). 2022 Apr 26;14(9):2164. doi: 10.3390/cancers14092164.
The composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies.
肿瘤微环境（TME）的组成介导了恶性胸膜间皮瘤（MPM）化疗和免疫治疗的结果。肿瘤相关巨噬细胞（TAM）和单核细胞髓系来源的免疫抑制细胞（M-MDSC）构成了TME的主要部分。作为先天免疫系统的核心细胞，单核细胞发挥着吞噬作用、细胞因子产生以及抗体依赖性细胞介导的细胞毒性（ADCC）等已明确的功能。本研究的目的是评估单核细胞通过与MPM细胞进行细胞间接触发挥直接细胞毒性的能力。实验模型基于通过阴性分选的人血单核细胞与间皮瘤细胞系之间的共培养。数据显示：（i）人血单核细胞通过直接细胞间接触诱导肿瘤细胞死亡；（ii）丙戊酸（VPA）是这种细胞毒性活性的药理学增强剂；（iii）VPA增加单核细胞迁移及其与MPM细胞的聚集；（iv）VPA调节单核细胞背后的分子机制涉及与M2表型相关的膜受体下调，即CD163、CD206和CD209。因此，这些结论拓宽了我们对肿瘤微环境免疫监视所涉及分子机制的理解，并为仍不尽人意的MPM治疗的进一步改善开辟了新前景。
