American Association for Cancer Research
Browse
mct-21-0743_supplementary_table_8_supps8.xlsx (5.86 MB)

Supplementary Table from Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Download (5.86 MB)
dataset
posted on 2023-04-03, 18:44 authored by Pavlina Spiliopoulou, Sarah Spear, Hasan Mirza, Ian Garner, Lynn McGarry, Fabio Grundland-Freile, Zhao Cheng, Darren P. Ennis, Nayana Iyer, Sophie McNamara, Marina Natoli, Susan Mason, Karen Blyth, Peter D. Adams, Patricia Roxburgh, Matthew J. Fuchter, Bob Brown, Iain A. McNeish
Supplementary Table from Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma

Funding

NIHR Imperial Biomedical Research Centre

National Institute for Health Research

Find out more...

Ovarian Cancer Action

Cancer Research UK

History

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 tumor 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 while suppressing tumor-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 tumors and resulted in tumor burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumor growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

Usage metrics

    Molecular Cancer Therapeutics

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC