MYCN Drives a Tumor Immunosuppressive Environment Which Impacts Survival in Neuroblastoma

Abstract

A wide range of malignancies presents <i>MYCN</i> amplification (MNA) or dysregulation. <i>MYCN</i> is associated with poor prognosis and its over-expression leads to several dysregulations including metabolic reprogramming, mitochondria alteration, and cancer stem cell phenotype. Some hints suggest that <i>MYCN</i> overexpression leads to cancer immune-escape. However, this relationship presents various open questions. Our work investigated in details the relationship of <i>MYCN</i> with the immune system, finding a correlated immune-suppressive phenotype in neuroblastoma (NB) and different cancers where <i>MYCN</i> is up-regulated. We found a downregulated Th1-lymphocytes/M1-Macrophages axis and upregulated Th2-lymphocytes/M2-macrophages in MNA NB patients. Moreover, we unveiled a complex immune network orchestrated by N-Myc and we identified 16 genes modules associated to MNA NB. We also identified a <i>MYCN</i>-associated immune signature that has a prognostic value in NB and recapitulates clinical features. Our signature also discriminates patients with poor survival in non-MNA NB patients where <i>MYCN</i> expression is not discriminative. Finally, we showed that targeted inhibition of <i>MYCN</i> by BGA002 (anti-<i>MYCN</i> antigene PNA) is able to restore NK sensibility in <i>MYCN</i>-expressing NB cells. Overall, our study unveils a <i>MYCN-</i>driven immune network in NB and shows a therapeutic option to restore sensibility to immune cells.