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

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)-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 MYCN-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 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-γ, 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.

SUBMITTER: Seier JA

PROVIDER: S-EPMC8141444 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.MethodsCandidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.ResultsWe reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also.ConclusionWe reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.