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

• DOI: 10.1126/sciadv.abo8043
• Publication Date: 2022-10-05T17:57:20Z
• Authors: Andrea Piunti; Khyati Meghani; Yanni Yu; A. Gordon Robertson; Joseph R. Podojil; Kimberly A. McLau...; Zonghao You; Damiano Fantini; MingYi Chiang; Yi Luo; Lu Wang; Nathan Heyen; Jun Qian; Stephen D. Miller; Ali Shilatifard; Joshua J. Meeks
• Keywords: Carcinoma, Transitional Cell; 0303 health sciences; 610; 3. Good health; Mice; 03 medical and health sciences; Urinary Bladder Neoplasms; Cell Line, Tumor; Carcinogens; Histone Methyltransferases; Animals; Enhancer of Zeste Homolog 2 Protein; Biomedicine and Life Sciences

The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because innate resistance to treatment. We identified elevated expression the histone methyltransferase EZH2 as a hallmark aggressive UCa and hypothesized that inhibition, via small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, carcinogen-induced mouse bladder cancer model, reduction tumor progression an increase immune infiltration upon inhibition were observed. Treatment mice EZH2i causes MHC class II urothelium can activate infiltrating T cells. Unexpectedly, we found lack intact adaptive system completely abolishes induced by inhibition. These findings show evasion only important determinant for efficacy treatment model.