Journal article
Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma
Science advances, Vol.8(40), pp.eabo8043-eabo8043
10/05/2022
DOI: 10.1126/sciadv.abo8043
PMCID: PMC9534493
PMID: 36197969
Abstract
The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.
EZH2 inhibition in bladder cancer strongly reduces tumor progression only through suppression of an adaptive immune response.
Details
- Title: Subtitle
- Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma
- Creators
- Andrea Piunti - University of ChicagoKhyati Meghani - Northwestern UniversityYanni Yu - Northwestern UniversityA. Gordon Robertson - Dxige Research Inc., Courtenay, BC, Canada.Joseph R. Podojil - Northwestern UniversityKimberly A. McLaughlin - Northwestern UniversityZonghao You - Northwestern UniversityDamiano Fantini - Northwestern UniversityMingYi Chiang - Northwestern UniversityYi Luo - University of IowaLu Wang - Northwestern UniversityNathan Heyen - Northwestern UniversityJun Qian - Northwestern UniversityStephen D. Miller - Northwestern UniversityAli Shilatifard - Northwestern UniversityJoshua J. Meeks - Northwestern University
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.8(40), pp.eabo8043-eabo8043
- DOI
- 10.1126/sciadv.abo8043
- PMID
- 36197969
- PMCID
- PMC9534493
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Publisher
- American Association for the Advancement of Science
- Grant note
- BX003692 / ; BX005599 / ; K99CA234434 / ;
- Alternative title
- Immune activation by EZH2i
- Language
- English
- Date published
- 10/05/2022
- Academic Unit
- Urology
- Record Identifier
- 9984321433302771
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