A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Melissa M Phillips, Iuliia Pavlyk, Michael Allen, Essam Ghazaly, Rosalind Cutts, Josephine Carpentier, Joe Scott Berry, Callum Nattress, Shenghui Feng, Gunnel Hallden, Claude Chelala, John Bomalaski, Jeremy Steele, Michael Sheaff, Frances Balkwill, Peter W Szlosarek
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 75 Issue 3 Pg. 570-584 (Jun 2023) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 37010783 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• ADI PEG20
• Arginine
• Argininosuccinate Synthase
• Polyethylene Glycols
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Humans
• Mice
• Arginine (metabolism)
• Argininosuccinate Synthase (genetics, metabolism)
• Cell Line, Tumor
• Mesothelioma (drug therapy, genetics)
• Mesothelioma, Malignant
• Neoplasm Recurrence, Local
• Polyethylene Glycols (pharmacology)
• Tumor Microenvironment
• Vascular Endothelial Growth Factor A
• Macrophages
• Drug Resistance, Neoplasm