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Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma
Title: | Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma |
Authors: | McNeish, I Spiliopoulou, P Spear, S Mirza, H Garner, I Grundland-freile, F Cheng, Z Ennis, D Iyer, N McNamara, S Natoli, M Fuchter, M Brown, R |
Item Type: | Journal Article |
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. |
Issue Date: | 7-Feb-2022 |
Date of Acceptance: | 4-Feb-2022 |
URI: | http://hdl.handle.net/10044/1/95162 |
DOI: | 10.1158/1535-7163.MCT-21-0743 |
ISSN: | 1535-7163 |
Publisher: | American Association for Cancer Research |
Start Page: | 522 |
End Page: | 534 |
Journal / Book Title: | Molecular Cancer Therapeutics |
Volume: | 21 |
Issue: | 4 |
Copyright Statement: | © 2022 The Author(s); Published by the American Association for Cancer Research. This work is licensed under a Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/) |
Sponsor/Funder: | Imperial College Healthcare NHS Trust- BRC Funding Imperial College Healthcare NHS Trust- BRC Funding Imperial College Healthcare NHS Trust- BRC Funding Ovarian Cancer Action Imperial College Healthcare NHS Trust- BRC Funding National Institute for Health Research Engineering & Physical Science Research Council (EPSRC) |
Funder's Grant Number: | RDF03 RDB01 RDB01 n/a RDB01 NIHR202372 EP/R00188X/1 |
Keywords: | Animals Carcinoma, Ovarian Epithelial Cystadenocarcinoma, Serous Enhancer of Zeste Homolog 2 Protein Epigenesis, Genetic Humans Immunity Mice Ovarian Neoplasms Prognosis Tumor Microenvironment Oncology & Carcinogenesis 1112 Oncology and Carcinogenesis 1115 Pharmacology and Pharmaceutical Sciences |
Publication Status: | Published |
Online Publication Date: | 2022-02-07 |
Appears in Collections: | Department of Surgery and Cancer Chemistry Faculty of Medicine Faculty of Natural Sciences |
This item is licensed under a Creative Commons License