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

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.

• Authors: 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 Burchill, Michelle Haber, Carmela De Santo, Francis Mussai
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 3 Pg. 611-624 (02 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 30545920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Interleukin-1beta
• TNF protein, human
• Tumor Necrosis Factor-alpha
• Arginine
• ARG2 protein, human
• Arginase

Topics

• Animals
• Arginase (metabolism)
• Arginine (metabolism)
• Cell Line, Tumor
• Humans
• Interleukin-1beta (immunology, metabolism)
• MAP Kinase Signaling System
• Macrophages (immunology, metabolism, pathology)
• Mice
• Mice, Transgenic
• Myeloid Cells (immunology, metabolism, pathology)
• Neuroblastoma (immunology, metabolism, pathology)
• Sarcoma, Ewing (immunology, metabolism, pathology)
• Tumor Microenvironment
• Tumor Necrosis Factor-alpha (immunology, metabolism)