Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression
Autor: | Puri Fortes, José A. Casado, Jesús M. Paramio, Obdulia Rabal, Cristian Suárez-Cabrera, Marta Dueñas, Cristina Segovia, Carmen Segrelles, Noelia Casares, Juan José Lasarte, Xabier Agirre, Felix Guerrero-Ramos, Iris Lodewijk, Ester Munera-Maravilla, Amaia Vilas-Zornoza, Leire Garate, Guillermo Velasco, Edurne San José-Enériz, Julen Oyarzabal, Mónica Martínez-Fernández, Estíbaliz Miranda, Fernando F. López-Calderón, Alejandra Bernardini, Luis Vitores Valcárcel, Felipe Villacampa, Daniel Castellano, Carolina Rubio, Felipe Prosper |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Programmed cell death medicine.medical_treatment Programmed Cell Death 1 Receptor General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Immune system Cell Line Tumor Histocompatibility Antigens medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Cisplatin Bladder cancer business.industry Histone-Lysine N-Methyltransferase General Medicine Immunotherapy medicine.disease Immune checkpoint Editorial Commentary 030104 developmental biology Urinary Bladder Neoplasms Apoptosis 030220 oncology & carcinogenesis Cancer research Immunogenic cell death Female business medicine.drug |
Zdroj: | Translational Cancer Research |
ISSN: | 1546-170X 1078-8956 |
Popis: | Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5–8. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1−/−) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade. Inhibition of histone and DNA methyltransferase activity enhances sensitivity to platinum-based and immunotherapy in a novel transgenic mouse model of metastatic bladder cancer. |
Databáze: | OpenAIRE |
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