近日，来自西班牙的多个研究组合作揭示了抑制G9a/DNMT通路可激活免疫介导的膀胱癌清除。2019年7月出版的《自然—医学》发表了这项成果。

研究人员发现高G9a (EHMT2)表达与膀胱癌的临床预后不良有关，而通过一个新的抑制剂(CM-272)靶向G9a/DNMT甲基转移酶活性可诱导细胞凋亡和免疫原性细胞死亡。通过使用具有正常免疫力的四基因敲除（Pten、Trp53、Rb1、Rbl1）的恶性膀胱癌肌肉转移转基因小鼠模型，研究人员证实CM-272与顺铂联用治疗能够显著性地消除原发灶与转移灶。当CM-272与anti-PD-L1联用时，抗肿瘤效果甚至能在不使用顺铂时显著提升。这些疗效与内源性的肿瘤免疫反应和免疫原性细胞死亡有关，其将免疫不响应的肿瘤转变为免疫响应的肿瘤。

研究人员发现，膀胱癌病人队列中G9a的表达增加与PD-L1抑制的耐药性相关。综上所述，这些发现为表观遗传抑制剂与免疫检查点阻断联用治疗膀胱癌提供了新的希望。

附：英文原文

Title: Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression

Author: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

Issue&Volume: Volume 25 Issue 7, July 2019

Abstract: Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients. 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.

DOI: 10.1038/s41591-019-0499-y

Source:https://www.nature.com/articles/s41591-019-0499-y