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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.

Author information

1
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
2
Children's Cancer Institute, University of New South Wales, Sydney, Australia.
3
Children's Cancer Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
4
School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Nottingham, UK.
5
The Institute of Cancer Research, London, UK.
6
Institute of Cancer Genomic Sciences, University of Birmingham, Birmingham, Birmingham, UK.
7
Bio-Cancer Treatment International, Hong Kong.
8
GMGF, Aix Marseille University, INSERM, Marseille, France.
9
Sciomics GmbH, Heidelberg, Germany.
10
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. francis.mussai@nhs.net.

Abstract

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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