Epigenetic state determines inflammatory sensing in neuroblastoma.

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.

BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states.

The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of one Bptf allele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). High BPTF levels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation of BPTF and CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.

Refining immunotherapeutic approaches to high-risk neuroblastoma based on tumor genomic profiles.

In this issue, Coronado et al. attempt to improve our understanding of the factors affecting the response to immunotherapy in a large subset of high-risk neuroblastoma with hemizygous deletion of chromosome 11q. By using several computational approaches, the authors study potential transcriptional and post-transcriptional pathways that may affect the response to immunotherapy and further be leveraged therapeutically in a biomarker-directed fashion.

Egg Food Challenges are Associated with More Gastrointestinal Reactions.

Egg allergy is a common pediatric allergy, and is usually outgrown by elementary school age. There is, therefore, a need to perform an oral food challenge (OFC) to establish the presence of food allergy to egg. In this study, we conducted a retrospective review of 2304 OFCs at a pediatric center and analyzed the severity of reactions during egg OFCs and compared them with other foods. The gastrointestinal system (GI) has been reported as more affected in egg food challenge. This study confirmed that 11% of patients undergoing egg OFC had GI symptoms vs. 7% undergoing food challenges for other foods or compared to milk, peanut and tree nut, individually. However, the involvement of lower respiratory tract was less frequent with egg than observed in peanut and tree nut OFC and similar to observed rate in milk. In conclusion, our study confirmed that OFC to egg causes more GI symptoms and less respiratory symptoms compared to other foods, in particular peanuts and tree nuts. However, 27% of children who failed egg OFC had lower respiratory tract reactions and required the use of epinephrine, similarly to children undergoing milk challenge.