Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression Article Swipe
Julian P. Layer
,
Marie T. Kronmüller
,
Thomas Quast
,
Debby van den Boorn-Konijnenberg
,
Maike Effern
,
Daniel Hinze
,
Kristina Althoff
,
Alexander Schramm
,
Frank Westermann
,
Martin Peifer
,
Gunther Hartmann
,
Thomas Tüting
,
Waldemar Kolanus
,
Matthias Fischer
,
Johannes H. Schulte
,
Michael Hölzel
·
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1080/2162402x.2017.1320626
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1080/2162402x.2017.1320626
Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity. Using an integrative transcriptomic approach, we investigated the molecular characteristics of T-cell infiltration in primary neuroblastomas as an indicator of pre-existing immune responses and potential responsiveness to checkpoint inhibition. Here, we report that a T-cell-poor microenvironment in primary metastatic neuroblastomas is associated with genomic amplification of the MYCN (N-Myc) proto-oncogene. These tumors exhibited lower interferon pathway activity and chemokine expression in line with reduced immune cell infiltration. Importantly, we identified a global role for N-Myc in the suppression of interferon and pro-inflammatory pathways in human and murine neuroblastoma cell lines. N-Myc depletion potently enhanced targeted interferon pathway activation by a small molecule agonist of the cGAS-STING innate immune pathway. This promoted chemokine expression including Cxcl10 and T-cell recruitment in microfluidics migration assays. Hence, our data suggest N-Myc inhibition plus targeted IFN activation as adjuvant strategy to enforce cytotoxic T-cell recruitment in MYCN-amplified neuroblastomas.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1080/2162402x.2017.1320626
- https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1320626?needAccess=true
- OA Status
- gold
- Cited By
- 128
- References
- 64
- Related Works
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- OpenAlex ID
- https://openalex.org/W2608700009
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W2608700009Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1080/2162402x.2017.1320626Digital Object Identifier
- Title
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Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expressionWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2017Year of publication
- Publication date
-
2017-04-28Full publication date if available
- Authors
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Julian P. Layer, Marie T. Kronmüller, Thomas Quast, Debby van den Boorn-Konijnenberg, Maike Effern, Daniel Hinze, Kristina Althoff, Alexander Schramm, Frank Westermann, Martin Peifer, Gunther Hartmann, Thomas Tüting, Waldemar Kolanus, Matthias Fischer, Johannes H. Schulte, Michael HölzelList of authors in order
- Landing page
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https://doi.org/10.1080/2162402x.2017.1320626Publisher landing page
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https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1320626?needAccess=trueDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1320626?needAccess=trueDirect OA link when available
- Concepts
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Cancer research, CXCL10, Chemokine, Tumor microenvironment, Neuroblastoma, Immunotherapy, Interferon, Immune checkpoint, Immune system, Biology, T cell, Immunology, Cytotoxic T cell, Medicine, Cell culture, Genetics, In vitro, BiochemistryTop concepts (fields/topics) attached by OpenAlex
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128Total citation count in OpenAlex
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2025: 10, 2024: 20, 2023: 20, 2022: 33, 2021: 24Per-year citation counts (last 5 years)
- References (count)
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64Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| primary_location.raw_source_name | OncoImmunology |
| primary_location.landing_page_url | https://doi.org/10.1080/2162402x.2017.1320626 |
| publication_date | 2017-04-28 |
| publication_year | 2017 |
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