Epigenetic state determines inflammatory sensing in neuroblastoma

Adam J. Wolpaw, Liron D. Grossmann, Jessica L. Dessau, May M. Dong, Bailey J. Aaron, Patricia A. Brafford, Darya Volgina, Guillem Pascual-Pasto, Alba Rodriguez-Garcia, Yasin Uzun, Marie Arsenian-Henriksson, Daniel J. Powell, Kristopher R. Bosse, Andrew Kossenkov, Kai Tan, Michael D. Hogarty, John M. Maris, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Immunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically “cold” pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling, and all but one lack functional cytosolic DNA sensing via cGAS-STING. However, double-stranded RNA (dsRNA) sensing via Toll-like receptor 3 (TLR3) was heterogeneous, as was signaling through other dsRNA sensors and TLRs more broadly. Seven cell lines showed robust response to dsRNA, six of which are in the mesenchymal epigenetic state, while all unresponsive cell lines are in the adrenergic state. Genetically switching adrenergic cell lines toward the mesenchymal state fully restored responsiveness. In responsive cells, dsRNA sensing results in the secretion of proinflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T cells in vitro. Using single-cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intratumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.

Original languageEnglish (US)
Article numbere2102358119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - Feb 8 2022

All Science Journal Classification (ASJC) codes

  • General


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