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

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.

Science advances. 2022 Oct 05 [Epub]

Andrea Piunti, Khyati Meghani, Yanni Yu, A Gordon Robertson, Joseph R Podojil, Kimberly A McLaughlin, Zonghao You, Damiano Fantini, MingYi Chiang, Yi Luo, Lu Wang, Nathan Heyen, Jun Qian, Stephen D Miller, Ali Shilatifard, Joshua J Meeks

Division of Hematology/Oncology, Department of Pediatrics, University of Chicago, Chicago, IL, USA., Department of Biochemistry and Molecular Genetics, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Dxige Research Inc., Courtenay, BC, Canada., Department of Microbiology and Immunology, Feinberg School of Medicine, Chicago, IL, USA., Department of Urology, University of Iowa, Iowa City, IA, USA.

Read an Expert Commentary by Bishoy Faltas, MD

email news signup