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Therapeutic anti-glioma effect of the combined action of PCSK inhibitor with the anti-tumoral factors secreted by Poly (I:C)-stimulated macrophages
Cancer Gene Therapy ( IF 6.4 ) Pub Date : 2021-01-05 , DOI: 10.1038/s41417-020-00286-1
Mélanie Rose 1, 2 , Marie Duhamel 1 , Soulaimane Aboulouard 1 , Firas Kobeissy 3 , Dominique Tierny 2 , Isabelle Fournier 1, 4 , Franck Rodet 1 , Michel Salzet 1, 4
Affiliation  

Macrophages plasticity is a key feature in cancer progression. Neoplastic cells can alter their immune functions and orient them into a pro-tumoral phenotype. In this context, we developed a new therapeutic strategy to switch macrophages phenotype and reactivate their anti-tumoral functions. We showed a dual activity of a proprotein convertases inhibitor as anti-glioma drug and anti-tumoral macrophages’ reactivation drug. Proprotein convertases are proteases that cleave proteins into functional proteins. Several of their substrates are involved in tumorigenesis and immunosuppression. We combine here proprotein convertases inhibitor with Poly (I:C), a TLR3 ligand, to increase the anti-tumoral activity of macrophages. With mass spectrometry-based proteomics, system biology, combined with biological assays, we established that a stimulation of macrophages with Poly (I:C) increased their secretion of pro-inflammatory cytokines and anti-tumoral factors. 3D invasion assay showed the efficacy of these anti-tumoral factors against mixed glioma cells and macrophages spheroids. Besides, immunofluorescence and proliferation assays showed an additive effect of the proprotein convertases inhibitor and the anti-tumoral factors secreted by Poly (I:C)-treated macrophages on both anti-glioma activity and macrophages anti-tumoral orientation directly in tumor microenvironment, leading to an innovative glioma therapy.



中文翻译:

PCSK 抑制剂与 Poly (I:C) 刺激的巨噬细胞分泌的抗肿瘤因子联合作用的抗胶质瘤治疗作用

巨噬细胞可塑性是癌症进展的一个关键特征。肿瘤细胞可以改变它们的免疫功能并将它们定向为促肿瘤表型。在此背景下,我们开发了一种新的治疗策略来改变巨噬细胞表型并重新激活其抗肿瘤功能。我们展示了前蛋白转化酶抑制剂作为抗神经胶质瘤药物和抗肿瘤巨噬细胞再激活药物的双重活性。前蛋白转化酶是将蛋白质切割成功能性蛋白质的蛋白酶。它们的几种底物与肿瘤发生和免疫抑制有关。我们在此将前蛋白转化酶抑制剂与 Poly (I:C)(一种 TLR3 配体)相结合,以增加巨噬细胞的抗肿瘤活性。以质谱为基础的蛋白质组学、系统生物学,结合生物检测,我们确定用 Poly (I:C) 刺激巨噬细胞会增加促炎细胞因子和抗肿瘤因子的分泌。3D 侵袭试验显示了这些抗肿瘤因子对混合胶质瘤细胞和巨噬细胞球体的功效。此外,免疫荧光和增殖试验显示,前蛋白转化酶抑制剂和 Poly (I:C) 处理的巨噬细胞分泌的抗肿瘤因子对肿瘤微环境中的抗神经胶质瘤活性和巨噬细胞抗肿瘤定向具有累加效应,导致创新的神经胶质瘤疗法。

更新日期:2021-01-05
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