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

Autor: Phillips MM; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK.; Department of Medical Oncology, Barts Health NHS Trust, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK., Pavlyk I; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Allen M; Center for Tumor Microenvironment, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Ghazaly E; Centre for Haemato-Oncology, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK.; Medicines and Healthcare Products Regulatory Agency (MHRA), London, UK., Cutts R; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Carpentier J; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Berry JS; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Nattress C; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Feng S; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Hallden G; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Chelala C; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Bomalaski J; Polaris Pharmaceuticals, Inc., San Diego, CA, 92121, USA., Steele J; Department of Medical Oncology, Barts Health NHS Trust, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK., Sheaff M; Department of Histopathology, Barts Health NHS Trust, Royal London Hospital, London, E1 1BB, UK., Balkwill F; Center for Tumor Microenvironment, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK., Szlosarek PW; Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)-a Cancer Research UK Center of Excellence, Queen Mary University of London, John Vane Science Center, London, EC1M 6BQ, UK. p.w.szlosarek@qmul.ac.uk.; Department of Medical Oncology, Barts Health NHS Trust, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK. p.w.szlosarek@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Pharmacological reports : PR [Pharmacol Rep] 2023 Jun; Vol. 75 (3), pp. 570-584. Date of Electronic Publication: 2023 Apr 03.
DOI: 10.1007/s43440-023-00480-6
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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