cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance

Dye, I.; Laing, S.; Garner, I.; Mirza, H. B.; Iyer, N.; Brady, N.; Spiliopoulou, P.; Spear, S.; Robinson, J.; Fiorentino, F.; Fuchter, M. J.; Murphy, D. J.; McNeish, I. J.; Brown, R.

doi:10.1101/2023.10.18.562888

bioRxiv · 10.1101/2023.10.18.562888

cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance

Dye, I.·Laing, S.·Garner, I.·Mirza, H. B.·Iyer, N.·Brady, N.·Spiliopoulou, P.·Spear, S.·Robinson, J.·Fiorentino, F.·Fuchter, M. J.·Murphy, D. J.·McNeish, I. J.·Brown, R.

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Abstract

Aberrant cMYC activity is a key driver of cancer, involved in several hallmark processes. Alongside the canonical hallmark of proliferation, cMYC represses immune signalling in a cell-intrinsic manner. The histone methyltransferases EZH2 and G9a interact with cMYC to modulate gene expression, including repression of immune genes via H3K27 and H3K9 histone methylation. Analyses of 565 cell lines derived from solid cancers demonstrated that greater cMYC-G9a/EZH2-mediated repression correlates with lower immune gene scores in a cell-intrinsic manner (innate, Type I and Type II IFN response), an effect most evident in MYC-amplified cell lines. In ovarian high-grade serous carcinoma (HGSC) cell lines and an in vivo murine model of HGSC, HKMTi-1-005, an inhibitor of H3K27/H3K9 methylation maintenance, relieved cMYC-G9a/EZH2 repression whilst inducing an immune response. A 7-gene immune signature (7ISG), related to viral mimicry signalling, is at the core of the HGSC immune response to HKMTi-1-005. In MYC-amplified HGSC patients, a low 7ISG score was associated with poor survival. Additionally, MYC-amplified cell lines were significantly more sensitive to HKMTi-1-005, whilst a low 7ISG score was associated with greater HKMTi-1-005 sensitivity, effects that were independent of canonical cMYC transcriptional activation. Examining the effects of HKMTi-1-005 treatment in a MYC-deregulated lung adenocarcinoma (LuAd) revealed induction of an immune response in vitro and prolonged survival in vivo. This suggests that inhibition of H3K27/H3K9 methylation maintenance will have efficacy in cMYC-deregulated tumours with low 7ISG scores, via disruption of cMYC-mediated repression of cell autonomous immune signalling and induction of an anti-tumour immune response. Statement of significanceOver 70% of cancers are cMYC-deregulated. We show that inhibition of H3K27/H3K9 methylation maintenance relieves cMYC-dependent immune repression and prolongs survival of animal tumour models, suggesting a novel approach to treating cMYC-deregulated tumours.

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Dye, I., Laing, S., Garner, I., Mirza, H. B., Iyer, N., Brady, N., Spiliopoulou, P., Spear, S., Robinson, J., Fiorentino, F., Fuchter, M. J., Murphy, D. J., McNeish, I. J., Brown, R.. 2023-10-20. cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance. https://doi.org/10.1101/2023.10.18.562888

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