Abstract 5214: Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma

Abstract

Abstract Immunotherapy remains a promising approach in the treatment of high-risk neuroblastoma, however efficacy is hampered by the immunosuppressive tumor microenvironment. We previously reported a link between intratumoral copper levels and Programmed Death-Ligand 1 (PD-L1) expression and therefore sought to elucidate the wider impact of copper chelation on immune evasion strategies (Voli et al 2020). Here we profile key elements of the neuroblastoma tumor microenvironment which work in concert to promote immunosuppression and tumor progression. Using the murine TH-MYCN model, animals were treated daily with the copper chelation agent tetraethylenepentamine (TEPA) for seven days before tumor resection and processing. Transcriptome analyses using single-cell RNA-sequencing revealed copper chelation positively skewed the functional status of tumor, immune and stromal compartments to enhance the anti-tumor immune response. This was supported by a tissue microarray screen using NanoString Digital Spatial Profiling which identified increased immune cell infiltration and regions of active tumor killing. High-resolution mass-spectrometry detected upregulation of major histocompatibility complex (MHC) proteins and exclusive antigenic signatures in peptide repertoires. A multiplex cytokine array indicated an improved anti-tumorigenic response underscored by T cell and Natural Killer cell activation. Importantly, combination of copper chelation and anti-GD2 antibody therapy led to tumor regression and significantly improved survival in vivo. Collectively, this study demonstrates the ability of copper chelation to successfully mitigate tumoral immune evasion strategies while providing remarkable insight into neuroblastoma biology. Findings provide crucial evidence in support of combining clinically approved copper chelators with immunotherapy to improve outcomes for neuroblastoma patients. Citation Format: Jourdin R. Rouaen, Daniele Mercatelli, Federica Saletta, Ensieh M. Poursani, Jayne E. Murray, Nicodemus Tedla, Federico M. Giorgi, Orazio Vittorio. Copper chelation overcomes the immunosuppressive tumor microenvironment in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5214.