聚乙二醇化精氨酸去亚氨基酶（ADI-PEG20；pegargiminase）能够耗尽精氨酸，并改善缺乏精氨酰琥珀酸合酶1（ASS1）的恶性胸膜间皮瘤（MPM）患者的生存结果。优化基于ADI-PEG20的治疗需要更深入地了解抵抗机制，包括肿瘤微环境介导的机制。在这里，我们试图反向翻译通过PEGargiminase治疗复发的ASS1缺乏的MPM患者中增加的肿瘤巨噬细胞浸润。通过流式细胞术分析了ADI-PEG20处理的巨噬细胞-MPM肿瘤细胞系（2591、MSTO、JU77）共培养。对ADI-PEG20处理的MPM肿瘤细胞进行了基因表达谱分析的微阵列实验，并使用qPCR、ELISA和LC/MS验证巨噬细胞相关的基因“突变”。使用PEGargiminase治疗的MPM患者的血浆进行细胞因子和精氨酰琥珀酸分析。我们发现ASS1表达的巨噬细胞促进了ADI-PEG20处理的ASS1阴性MPM细胞系的存活能力。微阵列基因表达数据揭示了ADI-PEG20处理的MPM细胞系中一种优势的CXCR2依赖性趋化表征和VEGF-A和IL-1α的共表达。我们确认巨噬细胞中的ASS1是IL-1α诱导的，并且亚氨基琥珀酸浓度在细胞上清中翻了一倍，足以在ADI-PEG20的共培养条件下恢复MPM细胞的存活。为进一步验证，我们检测到PEG-ARG银杏酸治疗的MPM患者的血浆VEGF-A和CXCR2依赖性细胞因子升高，以及亚氨基琥珀酸的增加。最后，在MSTO异种移植小鼠模型中，脂质体克洛德龙可以减少ADI-PEG20驱动的巨噬细胞浸润，并显著抑制生长。总之，我们的数据表明，ADI-PEG20可诱导的细胞因子通过巨噬细胞协同精氨酰琥珀酸燃料来对抗ASS1缺失的间皮瘤。这种新型的基质介导的抵抗途径可以被用来优化针对间皮瘤和相关精氨酸依赖性癌症的精氨酸剥夺疗法。 2023 年。作者。

Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy.Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic "hits" were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM.We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model.Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.© 2023. The Author(s).