Macrophage-Derived IL1β and TNFα Regulate Arginine Metabolism in Neuroblastoma.
Embargo End Date
ICR Authors
Authors
Fultang, L
Gamble, LD
Gneo, L
Berry, AM
Egan, SA
De Bie, F
Yogev, O
Eden, GL
Booth, S
Brownhill, S
Vardon, A
McConville, CM
Cheng, PN
Norris, MD
Etchevers, HC
Murray, J
Ziegler, DS
Chesler, L
Schmidt, R
Burchill, SA
Haber, M
De Santo, C
Mussai, F
Gamble, LD
Gneo, L
Berry, AM
Egan, SA
De Bie, F
Yogev, O
Eden, GL
Booth, S
Brownhill, S
Vardon, A
McConville, CM
Cheng, PN
Norris, MD
Etchevers, HC
Murray, J
Ziegler, DS
Chesler, L
Schmidt, R
Burchill, SA
Haber, M
De Santo, C
Mussai, F
Document Type
Journal Article
Date
2019-02-01
Date Accepted
2018-12-05
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.
Citation
Cancer research, 2019, 79 (3), pp. 611 - 624
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
Research Team
Paediatric Solid Tumour Biology and Therapeutics