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Druggable epigenetic suppression of interferon-induced chemokine expression linked to amplification in neuroblastoma.

Journal for immunotherapy of cancer

Authors: Johanna A Seier, Julia Reinhardt, Kritika Saraf, Susanna S Ng, Julian P Layer, Dillon Corvino, Kristina Althoff, Frank A Giordano, Alexander Schramm, Matthias Fischer, Michael Hölzel

BACKGROUND: Amplification of the oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that 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)-γ 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 -driven malignant phenotype and repressors of IFN-γ transcriptional responses in NB cells. EHMT inhibitors enhanced IFN-γ-induced expression of the Th1-type chemokines and , key factors of T-cell recruitment into the TME. In -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-γ, in line with histone mark changes at and 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 -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, -amplified NBs) could promote a T-cell-infiltrated TME via enhanced Th1-type chemokine expression.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

PMID: 34016720

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