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A single-cell transcriptomic analysis of Neuroblastomas revealed a selective cGAS-STING pathway suppression in malignant cells (04b Atto di convegno in volume)

Sibilio Pasquale, DI GIULIO Stefano, Funari Alessio, Paci Paola, Veschi Veronica, Giannini Giuseppe

Neuroblastoma is a disease of disordered development accounting for 15% of childhood cancer deaths. The "cold"immunophenotype frequently occurring of these tumors is likely to contribute to its aggressiveness and refractoriness to treatments, including immune checkpoint blockade, observed in high risk neuroblastoma. The mechanisms that contribute to the cold immunostate have not been elucidated, yet. However, recent studies have reported the involvement of MYCN amplification in reducing the immune infiltrate in high-risk Neuroblastoma tumors. Its action mainly concerns suppressed interferon responses and pro-inflammatory pathways. An important pathway deputed to the activation of type I interferon responses and pro-inflammatory cytokines release is the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) cytosolic DNA sensing pathway. Recent preclinical studies suggest a promising therapeutic effect of cGAS-STING pathway reactivation in Neuroblastomas. However, very little is known about the regulation of the cGAS-STING pathway in Neuroblastoma malignant cells, and its relationship with the MYCN amplification state. To this end, we performed a single-cell transcriptomic analysis of primary human Neuroblastoma cells compared with their normal fetal and embryonic progenitors. The results of the high-resolution analysis of cGAS-STING pathway showed that Neuroblastomas malignant cells have a much lower expression of this pathway compared to normal progenitors and other cell phenotypes populating the tumor microenvironment, possibly acquiring an evolutionary advantage. Moreover, the cGAS-STING pathway anticorrelated with MYCN expression suggesting a putative regulatory mechanism of the STING pathway
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