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Native Chromatin Immunoprecipitation Using Murine Brain Tumor Neurospheres
Published on: January 29, 2018
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Epigenetic state determines inflammatory sensing in neuroblastoma
Adam J Wolpaw1,2,3, Liron D Grossmann4,2, Jessica L Dessau3
1Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; wolpawa@chop.edu cdang@lcr.org.
Summary
Neuroblastoma, a pediatric cancer, often fails immunotherapy. This study found that sensing double-stranded RNA (dsRNA) via Toll-like receptor 3 (TLR3) is key to immune response, with mesenchymal cells being responsive and adrenergic cells not.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy has transformed cancer care, yet many cancers, including neuroblastoma, remain resistant.
- Neuroblastoma is a pediatric cancer often characterized as immunologically
- cold,
- limiting the efficacy of current immunotherapeutic strategies.
Purpose of the Study:
- To investigate inflammatory signaling pathways in neuroblastoma.
- To identify mechanisms underlying neuroblastoma's resistance to immunotherapy.
- To explore the role of double-stranded RNA (dsRNA) sensing in neuroblastoma immune response.
Main Methods:
- Tested the functional response of 20 neuroblastoma cell lines to inflammatory stimuli.
- Assessed cytosolic DNA sensing via cGAS-STING and dsRNA sensing via TLR3.
- Utilized genetic manipulation to switch cell states and single-cell RNA sequencing.
Main Results:
- All cell lines possessed intact interferon signaling, but most lacked functional cytosolic DNA sensing (cGAS-STING).
- Double-stranded RNA (dsRNA) sensing via TLR3 was heterogeneous, with 7/20 cell lines responsive.
- Responsiveness to dsRNA correlated with the mesenchymal epigenetic state, while unresponsiveness was linked to the adrenergic state. Switching cell states restored dsRNA responsiveness.
- dsRNA sensing induced proinflammatory cytokine secretion, inflammatory gene expression, and enhanced T cell-mediated tumor killing in vitro.
- Mesenchymal neuroblastoma cells exhibited a higher basal inflammatory state.
Conclusions:
- Neuroblastoma's response to immunotherapy is linked to its inflammatory signaling pathways, particularly dsRNA sensing via TLR3.
- The mesenchymal epigenetic state is crucial for dsRNA sensing and inflammatory responses in neuroblastoma.
- Targeting TLR3 or promoting a mesenchymal state could enhance immunotherapy efficacy in neuroblastoma.
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