From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France;
From the ‡Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Université Lille 1, Cité Scientifique, 59655 Villeneuve D'Ascq, France.
Mol Cell Proteomics. 2018 Jun;17(6):1126-1143. doi: 10.1074/mcp.RA117.000443. Epub 2018 Mar 12.
High grade gliomas are the most common brain tumors in adult. These tumors are characterized by a high infiltration in microglial cells and macrophages. The immunosuppressive tumor environment is known to orient immune cells toward a pro-tumoral and anti-inflammatory phenotype. Therefore, the current challenge for cancer therapy is to find a way to reorient macrophages toward an antitumoral phenotype. Previously, we demonstrated that macrophages secreted antitumoral factors when they were invalidated for the proprotein converstase 1/3 (PC1/3) and treated with LPS. However, achieving an activation of macrophages via LPS/TLR4/Myd88-dependent pathway appears yet unfeasible in cancer patients. On the contrary, the antitumor drug Paclitaxel is also known to activate the TLR4 MyD88-dependent signaling pathway and mimics LPS action. Therefore, we evaluated if PC1/3 knock-down (KD) macrophages could be activated by Paclitaxel and efficient against glioma. We report here that such a treatment of PC1/3 KD macrophages drove to the overexpression of proteins mainly involved in cytoskeleton rearrangement. In support of this finding, we found that these cells exhibited a Ca increase after Paclitaxel treatment. This is indicative of a possible depolymerization of microtubules and may therefore reflect an activation of inflammatory pathways in macrophages. In such a way, we found that PC1/3 KD macrophages displayed a repression of the anti-inflammatory pathway STAT3 and secreted more pro-inflammatory cytokines. Extracellular vesicles isolated from these PC1/3 KD cells inhibited glioma growth. Finally, the supernatant collected from the coculture between glioma cells and PC1/3 KD macrophages contained more antitumoral factors. These findings unravel the potential value of a new therapeutic strategy combining Paclitaxel and PC1/3 inhibition to switch macrophages toward an antitumoral immunophenotype.
高级别神经胶质瘤是成人中最常见的脑肿瘤。这些肿瘤的特征是微胶质细胞和巨噬细胞的高度浸润。免疫抑制性肿瘤微环境已知会使免疫细胞向促肿瘤和抗炎表型转变。因此，癌症治疗的当前挑战是找到一种方法使巨噬细胞重新向抗肿瘤表型转变。以前，我们证明了当巨噬细胞被无效化的蛋白原转化酶 1/3（PC1/3）并经 LPS 处理时，它们会分泌抗肿瘤因子。然而，通过 LPS/TLR4/Myd88 依赖性途径激活巨噬细胞似乎在癌症患者中不可行。相反，抗肿瘤药物紫杉醇也已知可激活 TLR4 MyD88 依赖性信号通路并模拟 LPS 的作用。因此，我们评估了 PC1/3 敲低（KD）巨噬细胞是否可以被紫杉醇激活并有效抵抗神经胶质瘤。我们在这里报告说，这种 PC1/3 KD 巨噬细胞的治疗导致主要参与细胞骨架重排的蛋白质的过表达。支持这一发现，我们发现这些细胞在紫杉醇处理后表现出 Ca 增加。这表明微管可能发生解聚，因此可能反映了巨噬细胞中炎症途径的激活。通过这种方式，我们发现 PC1/3 KD 巨噬细胞显示抗炎途径 STAT3 的抑制和更多促炎细胞因子的分泌。从这些 PC1/3 KD 细胞中分离的细胞外囊泡抑制神经胶质瘤的生长。最后，从神经胶质瘤细胞与 PC1/3 KD 巨噬细胞的共培养物中收集的上清液含有更多的抗肿瘤因子。这些发现揭示了一种新的治疗策略的潜在价值，该策略结合紫杉醇和 PC1/3 抑制以将巨噬细胞转向抗肿瘤免疫表型。
