ArticlePharmacological reports : PR2023
A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.
Article in Pharmacological reports : PR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 5 citations in OpenAlex.
- Arginine metabolism, polyamine homeostasis and ferroptosis in cancer: Molecular links and therapeutic opportunities (Review).Molecular medicine reports · 2026Review
- Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan-Induced DNA Double-Strand Breaks in Uveal Melanoma.Pigment cell & melanoma research · 2026Article
- Metabolic vulnerabilities in pleural mesothelioma.Oncogenesis · 2026Review
- Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma.iScience · 2025Article
- Clinical Perspectives and Novel Preclinical Models of Malignant Pleural Mesothelioma: A Critical Review.ACS pharmacology & translational science · 2024Review
- Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.Frontiers in oncology · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundPegylated 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.
methodsMacrophage-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.
resultsWe 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.
conclusionsCollectively, 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.
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