Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression

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...

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Vydáno v:Oncoimmunology Ročník 6; číslo 6; s. e1320626
Hlavní autoři: Layer, Julian P., Kronmüller, Marie T., Quast, Thomas, Boorn-Konijnenberg, Debby van den, Effern, Maike, Hinze, Daniel, Althoff, Kristina, Schramm, Alexander, Westermann, Frank, Peifer, Martin, Hartmann, Gunther, Tüting, Thomas, Kolanus, Waldemar, Fischer, Matthias, Schulte, Johannes, Hölzel, Michael
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Taylor & Francis 03.06.2017
Taylor & Francis Group
Témata:
Chemokine
Cxcl10
immunotherapy
infiltration
interferoninfiltration
N-Myc
neuroblastoma
Original Research
STING
Chemokine
Cxcl10
interferoninfiltration
immunotherapy
N-Myc
neuroblastoma
STING
infiltration
ISSN:2162-402X, 2162-4011, 2162-402X
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Shrnutí: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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ISSN:2162-402X
2162-4011
2162-402X
DOI:10.1080/2162402X.2017.1320626