Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma [GeoMx]

Anti-disialoganglioside (GD2) antibody therapy has provided clinical benefit to patients with neuroblastoma however efficacy is likely impaired by the immunosuppressive tumor microenvironment. We have previously defined a link between intratumoral copper levels and immune evasion. Here, we report that adjuvant copper chelation potentiates anti-GD2 antibody therapy to confer durable tumor control in immunocompetent models of neuroblastoma. Mechanistic studies reveal copper chelation creates an immune-primed tumor microenvironment through enhanced infiltration and activity of Fc-receptor-bearing cells, specifically neutrophils which are emerging as key effectors of antibody therapy. Moreover, we report copper sequestration by neuroblastoma attenuates neutrophil function which can be successfully reversed using copper chelation to increase pro-inflammatory effector functions. Importantly, we repurpose the clinically approved copper chelating agent Cuprior as a non-toxic, efficacious immunomodulatory strategy. Collectively, our findings provide robust evidence for the clinical testing of Cuprior as an adjuvant to enhance the activity of anti-GD2 antibody therapy and improve outcomes for patients with neuroblastoma. A tissue microarray (TMA) was prepared using 20 Th-MYCN tumor samples (10 control, 10 TEPA-treated) in duplicate, cored at 1mm. Coring sites were chosen at random however areas exhibiting necrosis were excluded prior by an experienced histopathologist using a hematoxylin-eosin stain. The FFPE TMA block was sectioned at 4µm and transferred to a Bond Plus slide (Leica Biosystems, USA; #S21.2113.A) and were processed by the NanoString GeoMx DSP Technology Access Program.