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

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

Abstract

© 2018 American Association for Cancer Research. 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.

Citation

Burchill, S. A., Ziegler, D. S., Etchevers, H. C., Norris, M. D., Cheng, P. N., McConville, C. M., Berry, A. M., Gamble, L. D., Fultang, L., Gamble, L. D., Gneo, L., Berry, A. M., Egan, S. A., De Bie, F., Yogev, O., Eden, G. L., Booth, S., Brownhill, S., Vardon, A., McConville, C. M., …Mussai, F. (2019). Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma. Cancer Research, 79(3), 611-624. https://doi.org/10.1158/0008-5472.CAN-18-2139

• Journal Article Type: Article
• Acceptance Date: Dec 5, 2018
• Online Publication Date: Dec 19, 2018
• Publication Date: 2019-02
• Deposit Date: Jan 7, 2019
• Publicly Available Date: Jan 7, 2019
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 79
• Issue: 3
• Pages: 611-624
• DOI: https://doi.org/10.1158/0008-5472.CAN-18-2139
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/1447746
• Publisher URL: http://cancerres.aacrjournals.org/content/early/2018/12/19/0008-5472.CAN-18-2139
• Contract Date: Jan 7, 2019