dianas 8(1) > Munera-Maravilla etal

dianas | Vol 8 Num 1 | marzo 2019 | e201903a22

Improving immunotherapy through chromatin remodelers inhibitors in bladder cancer.

Ester Munera-Maravilla^a, Cristina Segovia, Edurne San José-Enériz, 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, Felix Guerrero, Guillermo de Velasco, Julen Oyarzabal, Daniel Castellano, Xabier Agirre, Felipe Prósper, Jesús M. Paramio

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) Av. Complutense, 40, 28040 Madrid.

a. ester.munera@ciemat.es

IV Congreso de Señalización Celular, SECUAH 2019.
20-22 de marzo, 2019. Universidad de Alcalá. Alcalá de Henares, Madrid. España.
Sesión A2, Cáncer.

Keywords: bladder cancer; epigenetics; immunotherapy

Abstract

Bladder cancer (BC) is a common neoplasm which is lethal in its advanced muscular invasive phase and given the very limited therapeutic advances in the field, is in urgent need of new treatments. Recent molecular characterization of BC has defined new genetic and epigenetic drivers of the disease and potential new targets. The introduction of immune checkpoint inhibitors in BC has shown remarkable efficacy but only in a limited fraction of patients. Here, we show that in human BC high expression of G9a (EHMT2), a H3K9 methyltransferase, is associated with poor clinical outcome and that the targeting of G9a/DNMT methyltransferase activity with a novel, reversible, potent and dual inhibitor (CM-272) induces apoptosis and immunogenic cell death. In vivo, CM-272 alone and particularly in combination with cisplatin (CDDP) improves survival in xenograft models of BC. Using an immunocompetent quadruple (PtenF/F; Trp53F/F; Rb1F/F;Rbl1-/-) knockout transgenic mouse model of highly aggressive metastatic muscle-invasive BC, we demonstrate that treatment with CM-272 and CDDP results in significant regression of tumors and metastases. The anti-tumor effect is significantly improved when CM-272 is combined with anti-PD-L1, even in the absence of CDDP. These effects are associated with an in vivo activation of an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, in a series of BC patients treated with PD1 inhibitors, we show that increased levels of G9a and H3K9me2 are associated with tumor resistance, suggesting that expression of G9a may be a biomarker of response to immunotherapy. In summary, these findings support new and promising opportunities for the treatment of BC patients using a combination of epigenetic inhibitors and immune checkpoint blockade.