Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression.
Oncoimmunology, 2017;6(6):e1320626.
Layer JP[1], Kronmüller MT[2], Quast T[2], van den Boorn-Konijnenberg D[1], Effern M[1, 3], Hinze D[1], Althoff K[4], Schramm A[4, 5], Westermann F[6], Peifer M[7, 8], Hartmann G[9], Tüting T[10, 11], Kolanus W[2], Fischer M[8, 12, 13], Schulte J[14], Hölzel M[1]
Affiliations
PMID: 28680756DOI: 10.1080/2162402X.2017.1320626
Abstract
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.
Keywords: Chemokine; Cxcl10; N-Myc; STING; immunotherapy; infiltration; interferoninfiltration; neuroblastoma
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