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

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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 Creative Commons