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Published October 5, 2022 | Version v1
Journal article Open

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Creators

  • 1. University of Chicago
  • 2. Northwestern University
  • 3. Dxige Research Inc.
  • 4. University of Iowa

Description

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.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All sequencing data have been deposited to GEO under the accession ID GSE209853. EPZ011989 was provided by Epizyme Inc. under a material transfer agreement. Requests for EPZ011989 should be submitted to M. J. Hinrichs at mary.jane.hinrichs@ipsen.com

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Additional details

Identifiers

DOI
10.1126/sciadv.abo8043
Other
oai:uchicago.tind.io:10918

Funding

Veterans Health Administration
BX003692
Veterans Health Administration
BX005599
National Cancer Institute
Transition to Independence Grant

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Pediatrics
Center(s) or Institute(s)
Comprehensive Cancer Center