Fig. 1

Overview of the interactions of myeloid cell subsets in the tumor microenvironment of neuroblastoma. A neuroblastoma tumor is shown in the center, surrounded by various myeloid immune cells: neutrophils, MDSC, monocytes, TAM, and eosinophils. For each of these cell types, pertinent interactions within the TME are depicted. For neutrophils, a high NLR is associated with unfavorable clinical outcomes. Reported tumor-neutrophil interactions involve the induction of neutrophil adhesion to neuroblastoma cell lines through IFNγ and IL-1, resulting in increased ICAM-1 expression on neutrophils. MDSCs are linked to T cell activation inhibition, notably through P2X7 receptor activation leading to increased ATP levels within the TME. Additionally, neuroblastoma-conditioned medium induces MDSCs through M-CSF and Arg-1/2. While most mouse MDSCs exhibit an M-MDSC phenotype, human MDSCs present a PMN-MDSC signature. For monocytes, LMR was not correlated with clinical outcomes in neuroblastoma patients. In neuroblastoma, TAMs undergo polarization from M1 to M2 as the disease progresses. Additionally, TAMs contribute to the preparation of the metastatic niche by taking up tumor-secreted EVs, resulting in the upregulation of immunosuppressive cytokines and genes associated with tumor cell extravasation, and via the CXCL2/CXCR2 axis. In MYCN-amplified neuroblastoma, TAMs exhibit elevated expression of macrophage-related immune checkpoints CD47 and Siglec7, in contrast to MYCN-nonamplified tumors. MYCN-nonamplified neuroblastoma is characterized by elevated CCL2 secretion by TAMs, resulting in the recruitment of TAMs, myeloid cells, and plasmacytoid DC. Furthermore, TAM-induced hypoxia leads to the inhibition of NK cells through HIF-2α production. TAMs also collaborate with CAFs and MSCs to promote tumor progression. Although our understanding of eosinophils, mast cells, and basophils is limited, IGF-2 secreted by eosinophils is suggested to play a role in neuroblastoma tumor growth. Abbreviations: Arg1/2 = arginase-1/2, ATP = adenosine triphosphate, CAF = cancer-associated fibroblast, CAF = cancer-associated fibroblasts, CCL2 = C–C motif chemokine ligand 2, CXCL2 = C-X-C motif chemokine ligand 2, CXCR2 = C-X-C motif chemokine receptor 2, DC = dendritic cell, Eo = eosinophil, EV = extracellular vesicles, EVs = extracellular vesicles, HIF-2a = hypoxia inducible factor 2α, ICAM-1 = intercellular adhesion molecule-1, IFNγ = interferon gamma, IGF-2 = insulin-like growth factor 2, LMR = lymphocyte-to-monocyte ratio, M-CSF = macrophage-colony stimulating factor, M-MDSC = monocytic myeloid-derived suppressor cells, MDSC = myeloid-derived suppressor cell, Mono = monocyte, MSC = mesenchymal stromal cell, MSC = mesenchymal stromal cells, NB = neuroblastoma, NB-NA = MYCN non-amplified neuroblastoma, Neutro = neutrophil, NK = natural killer, NLR = neutrophil-to-lymphocyte ratio, PMN-MDSC = polymorphonuclear myeloid-derived suppressor cells, TAM = tumor-associated macrophage, TME = tumor microenvironment