Universität zu Köln

Seier, Johanna A., Reinhardt, Julia, Saraf, Kritika, Ng, Susanna S., Layer, Julian P., Corvino, Dillon, Althoff, Kristina, Giordano, Frank A., Schramm, Alexander, Fischer, Matthias and Hoelzel, Michael (2021). Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma. J. Immunother. Cancer, 9 (5). LONDON: BMJ PUBLISHING GROUP. ISSN 2051-1426

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Abstract

Background Amplification of the MYCN oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that MYCN promotes a non-inflamed and T-cell infiltration-poor ('cold') tumor microenvironment (TME) by suppressing interferon signaling. This may explain, at least in part, why patients with NB seem to have little benefit from single-agent immune checkpoint blockade (ICB) therapy. Targeting MYCN or its effectors could be a strategy to convert a cold TME into a 'hot' (inflamed) TME and improve the efficacy of ICB therapy. Methods NB transcriptome analyses were used to identify epigenetic drivers of a T-cell infiltration-poor TME. Biological and molecular responses of NB cells to epigenetic drugs and interferon (IFN)-gamma exposure were assessed by proliferation assays, immunoblotting, ELISA, qRT-PCR, RNA-seq and ChIP-qPCR as well as co-culture assays with T cells. Results We identified H3K9 euchromatic histone-lysine methyltransferases EHMT2 and EHMT1, also known as G9a and GLP, as epigenetic effectors of the MYCN-driven malignant phenotype and repressors of IFN-gamma transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-gamma-induced expression of the Th1-type chemokines CXCL9 and CXCL10, key factors of T-cell recruitment into the TME. In MYCN-amplified NB cells, co-inhibition of EZH2 (enhancer of zeste homologue 2), a H3K27 histone methyltransferase cooperating with EHMTs, was needed for strong transcriptional responses to IFN-gamma, in line with histone mark changes at CXCL9 and CXCL10 chemokine gene loci. EHMT and EZH2 inhibitor response gene signatures from NB cells were established as surrogate measures and revealed high EHMT and EZH2 activity in MYCN-amplified high-risk NBs with a cold immune phenotype. Conclusion Our results delineate a strategy for targeted epigenetic immunomodulation of high-risk NBs, whereby EHMT inhibitors alone or in combination with EZH2 inhibitors (in particular, MYCN-amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Seier, Johanna A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Saraf, Kritika UNSPECIFIED UNSPECIFIED UNSPECIFIED Ng, Susanna S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Layer, Julian P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Corvino, Dillon UNSPECIFIED UNSPECIFIED UNSPECIFIED Althoff, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Giordano, Frank A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelzel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-578124
DOI:	10.1136/jitc-2020-001335
Journal or Publication Title:	J. Immunother. Cancer
Volume:	9
Number:	5
Date:	2021
Publisher:	BMJ PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2051-1426
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language METHYLTRANSFERASES G9A; SINGLE-ARM; OPEN-LABEL; TUMOR; METHYLATION; INHIBITOR Multiple languages Oncology; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57812