- [MOLECULAR THERAPEUTICS]
- [TRANSLATIONAL HEMATOLOGY]
- [IMMUNOLOGY AND IMMUNOTHERAPY]
- [IMMUNOMODULATION AND TUMOR MICROENVIRONMENT]
- [GENE THERAPY AND REGULATION OF GENE EXPRESSION]
Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression
Cristina Segovia, Edurne San José-Enériz, Ester Munera-Maravilla, Mónica Martínez-Fernández, Leire Garate, Estíbaliz Miranda, Amaia Vilas-Zornoza, Iris Lodewijk, Carolina Rubio, Carmen Segrelles, Luis Vitores Valcárcel, Obdulia Rabal, Noelia Casares, Alejandra Bernardini, Cristian Suarez-Cabrera, Fernando F López-Calderón, Puri Fortes, José A Casado, Marta Dueñas, Felipe Villacampa, Juan José Lasarte, Félix Guerrero-Ramos, Guillermo de Velasco, Julen Oyarzabal, Daniel Castellano, Xabier Agirre, Felipe Prósper, Jesús M Paramio
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.