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Cancer Res. 2019 Feb 1;79(3):611-624. doi: 10.1158/0008-5472.CAN-18-2139. Epub 2018 Dec 13.

Macrophage-Derived IL1β and TNFα Regulate Arginine Metabolism in Neuroblastoma.

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Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Children's Cancer Institute, University of New South Wales, Sydney, Australia.
Children's Cancer Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Nottingham, UK.
The Institute of Cancer Research, London, UK.
Institute of Cancer Genomic Sciences, University of Birmingham, Birmingham, Birmingham, UK.
Bio-Cancer Treatment International, Hong Kong.
GMGF, Aix Marseille University, INSERM, Marseille, France.
Sciomics GmbH, Heidelberg, Germany.
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.


Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1β and TNFα in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1β and TNFα established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1β and TNFα in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited. SIGNIFICANCE: These findings illustrate that cross-talk between myeloid cells and tumor cells creates a metabolic regulatory loop that promotes neuroblastoma progression.

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