Macrophage IL-1B and TNF-a create an immune-metabolic loop regulating Arginase2 in neuroblastoma

Abstract

International audienceNeuroblastoma is the most common solid tumour of childhood, yet the prognosis for high risk disease remains poor. We demonstrate that arginine metabolism via Arginase 2 (ARG2) drives neuroblastoma cell proliferation. Targeting arginine metabolism 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 delays tumour development and prolongs murine survival. Tumour cells polarise infiltrating monocytes to a M1- macrophage phenotype, which release IL-1 and TNF-a in an RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. Il-1 and TNF- signal-back to upregulate ARG2 expression via p38 and Extracellular regulated kinases 1/2 (ERK1/2) signalling in neuroblastoma and neural crest-derived cells. Proteomic analysis reveal Stage IV human tumour microenvironments are enriched in IL-1 and TNF-a, which is associated with a worse prognosis. Thus we describe an immune-metabolic regulatory loop between tumour cells and infiltrating myeloid cells regulating ARG2, which could clinically exploited. Statement of significance: Neuroblastoma polarised macrophages released IL-1and TNF which signal back to regulate Arginase2 in tumour cells and drive their proliferatio