Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high grade serous carcinoma

Spiliopoulou, P. et al. (2022) Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high grade serous carcinoma. Molecular Cancer Therapeutics, 21(4), pp. 522-534. (doi: 10.1158/1535-7163.MCT-21-0743) (PMID:35131874) (PMCID:PMC9377747)

Abstract

Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumours and resulted in tumour burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

• Item Type: Articles
• Additional Information: This work was funded by the NIHR Imperial Biomedical Research Centre (IAM: grant reference P74580, P74580-2 and P77646 – these grants did not support any animal experiments), Ovarian Cancer Action (IAM and BB: grant reference 006), Cancer Research UK (IAM, KB and PDA: grant references A17196, A29799, A15973, A17196, A12295) and the University of Glasgow endowments (PS). MJF would like to thank the Engineering and Physical Science Research Council for an Established Career Fellowship (EP/R00188X/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McGarry, Ms Lynn and Mcneish, Professor Iain and Blyth, Professor Karen and Spiliopoulou, Dr Pavlina and Ennis, Dr Darren and Adams, Professor Peter and Mason, Miss Susan and Roxburgh, Professor Patricia
• Authors: Spiliopoulou, P., Spear, S., Mirza, H., Garner, I., Iyer, N., McGarry, L., Grundland-Freile, F., Cheng, Z., Ennis, D. P., McNamara, S., Natoli, M., Mason, S., Blyth, K., Adams, P. D., Roxburgh, P., Fuchter, M. J., Brown, B., and McNeish, I. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cancer Therapeutics
• Publisher: American Association for Cancer Research
• ISSN: 1535-7163
• ISSN (Online): 1538-8514
• Published Online: 07 February 2022
• Copyright Holders: Copyright © 2022 American Association for Cancer Research
• First Published: First published in Molecular Cancer Therapeutics 21(4): 522-534
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
169615		Personalised biomarkers of response in high-grade serious ovarian cancer	Iain McNeish	Cancer Research UK (CRUK)	C608/A15973	CS - Clinical Research Garscube