Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma

Livingstone Fultang, Laura D Gamble, Luciana Gneo, Andrea M Berry, Sharon A Egan, Fenna De Bie, Orli Yogev, Georgina L Eden, Sarah Booth, Samantha Brownhill, Ashley Vardon, Carmel M McConville, Paul N Cheng, Murray D Norris, Heather C Etchevers, Jayne Murray, David S Ziegler, Louis Chesler, Ronny Schmidt, Susan A BurchillMichelle Haber, Carmela DeSanto, Francis Mussai

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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 a M1-macrophage phenotype, which released IL-1β and TNF-α in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL-1β and TNF-α 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 IL-1β and TNF-α 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.

Original languageEnglish
JournalCancer Research
Early online date13 Dec 2018
DOIs
Publication statusE-pub ahead of print - 13 Dec 2018

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