Macrophage-derived IL1B and TNFa regulate arginine metabolism in neuroblastoma

Livingstone Fultang, Laura D. Gamble, Luciana Gneo, Andrea M. Berry, Sharon A. Egan, Fenna De Bie, Orli Yogev, Georgina 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 De Santo, Francis Mussai

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa 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 IL1b and TNFa 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
Pages (from-to)611-624
Number of pages14
JournalCancer Research
Volume79
Issue number3
DOIs
Publication statusPublished - 1 Feb 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fultang, L., Gamble, L. D., Gneo, L., Berry, A. M., Egan, S. A., De Bie, F., ... Mussai, F. (2019). Macrophage-derived IL1B and TNFa regulate arginine metabolism in neuroblastoma. Cancer Research, 79(3), 611-624. https://doi.org/10.1158/0008-5472.CAN-18-2139