Universität zu Köln

Layer, Julian P., Kronmueller, Marie T., Quast, Thomas, van den Boorn-Konijnenberg, Debby, Effern, Maike ORCID: 0000-0002-1766-9881, Hinze, Daniel, Althoff, Kristina, Schramm, Alexander ORCID: 0000-0001-7670-7529, Westermann, Frank, Peifer, Martin ORCID: 0000-0002-5243-5503, Hartmann, Gunther ORCID: 0000-0003-1021-2018, Tueting, Thomas, Kolanus, Waldemar, Fischer, Matthias, Schulte, Johannes and Hoelzel, Michael (2017). Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression. OncoImmunology, 6 (6). PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 2162-402X

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Layer, Julian P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kronmueller, Marie T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quast, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED van den Boorn-Konijnenberg, Debby UNSPECIFIED UNSPECIFIED UNSPECIFIED Effern, Maike UNSPECIFIED orcid.org/0000-0002-1766-9881 UNSPECIFIED Hinze, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Althoff, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Alexander UNSPECIFIED orcid.org/0000-0001-7670-7529 UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Hartmann, Gunther UNSPECIFIED orcid.org/0000-0003-1021-2018 UNSPECIFIED Tueting, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolanus, Waldemar UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulte, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelzel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-246072
DOI:	10.1080/2162402X.2017.1320626
Journal or Publication Title:	OncoImmunology
Volume:	6
Number:	6
Date:	2017
Publisher:	TAYLOR & FRANCIS INC
Place of Publication:	PHILADELPHIA
ISSN:	2162-402X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYOCLONUS-ATAXIA SYNDROME; HIGH-RISK NEUROBLASTOMA; CHILDRENS CANCER GROUP; OPSOCLONUS-MYOCLONUS; PD-1 BLOCKADE; LUNG-CANCER; ANTINEURONAL ANTIBODIES; TUMOR MICROENVIRONMENT; CHECKPOINT BLOCKADE; STING ACTIVATION Multiple languages Oncology; Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24607