Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression.,Nature Medicine

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Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression.
Nature Medicine ( IF 58.7 ) Pub Date : 2019-07-03 , DOI: 10.1038/s41591-019-0499-y
Cristina Segovia _{1,

2,

3} , Edurne San José-Enériz _{2,

4} , Ester Munera-Maravilla _{1,

3} , Mónica Martínez-Fernández _{1,

2,

3,

5} , Leire Garate _{2,

6} , Estíbaliz Miranda _{2,

4} , Amaia Vilas-Zornoza _{2,

4} , Iris Lodewijk ₁ , Carolina Rubio _{2,

3} , Carmen Segrelles _{1,

2} , Luis Vitores Valcárcel _{2,

4,

7} , Obdulia Rabal ₈ , Noelia Casares ₉ , Alejandra Bernardini _{1,

2} , Cristian Suarez-Cabrera ₃ , Fernando F López-Calderón _{1,

2,

3} , Puri Fortes ₁₀ , José A Casado ₁₁ , Marta Dueñas _{1,

2,

3} , Felipe Villacampa _{2,

3} , Juan José Lasarte ₉ , Félix Guerrero-Ramos _{3,

12} , Guillermo de Velasco _{3,

13} , Julen Oyarzabal ₈ , Daniel Castellano _{1,

2,

13} , Xabier Agirre _{2,

4} , Felipe Prósper _{2,

4,

6} , Jesús M Paramio _{1,

2,

3}

Affiliation

Molecular Oncology Unit CIEMAT, Madrid, Spain.
Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
Institute of Biomedical Research, University Hospital '12 de Octubre', Madrid, Spain.
Hemato-oncology Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
Mobile Genomes and Disease Laboratory CIMUS, Universidad de Santiago de Compostela, La Coruña, Spain.
Hematology and Cell Therapy Department, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain.
TECNUN, University of Navarra, San Sebastián, Spain.
Small Molecule Discovery Platform, Molecular Therapeutics Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
Immunology and Immunotherapy Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
Division of Hematopoietic Innovative Therapies (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras and Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
Urology Department, University Hospital '12 de Octubre', Madrid, Spain.
Medical Oncology Department, University Hospital '12 de Octubre', Madrid, Spain.

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.

中文翻译：

G9a/DNMT 网络的抑制触发免疫介导的膀胱癌消退。

膀胱癌在其晚期、肌肉侵袭阶段是致命的，治疗进展非常有限1,2。最近的分子特征确定了膀胱癌的新（表观）遗传驱动因素和潜在靶点3、4。免疫检查点抑制剂已显示出显着的疗效，但仅限于少数膀胱癌患者 5-8。在这里，我们显示高 G9a (EHMT2) 表达与膀胱癌的不良临床结果相关，并且用新型抑制剂 (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。使用免疫活性四倍敲除 (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1-/-) 侵袭性转移性、肌肉浸润性膀胱癌的转基因小鼠模型，我们证明 CM-272 + 顺铂治疗导致已建立的肿瘤和转移瘤具有统计学意义的消退。当 CM-272 与抗程序性细胞死亡配体 1 联合使用时，即使在没有顺铂的情况下，抗肿瘤效果也会显着提高。这些效应与内源性抗肿瘤免疫反应和免疫原性细胞死亡有关，同时冷免疫肿瘤转化为热肿瘤。最后，在一组膀胱癌患者中，增加的 G9a 表达与对程序性细胞死亡蛋白 1 抑制的抗性有关。总之，这些发现支持使用表观遗传抑制剂和免疫检查点阻断的组合治疗膀胱癌的新的和有希望的机会。当 CM-272 与抗程序性细胞死亡配体 1 联合使用时，即使在没有顺铂的情况下，抗肿瘤效果也会显着提高。这些效应与内源性抗肿瘤免疫反应和免疫原性细胞死亡有关，同时冷免疫肿瘤转化为热肿瘤。最后，在一组膀胱癌患者中，增加的 G9a 表达与对程序性细胞死亡蛋白 1 抑制的抗性有关。总之，这些发现支持使用表观遗传抑制剂和免疫检查点阻断的组合治疗膀胱癌的新的和有希望的机会。当 CM-272 与抗程序性细胞死亡配体 1 联合使用时，即使在没有顺铂的情况下，抗肿瘤效果也会显着提高。这些效应与内源性抗肿瘤免疫反应和免疫原性细胞死亡有关，同时冷免疫肿瘤转化为热肿瘤。最后，在一组膀胱癌患者中，增加的 G9a 表达与对程序性细胞死亡蛋白 1 抑制的抗性有关。总之，这些发现支持使用表观遗传抑制剂和免疫检查点阻断的组合治疗膀胱癌的新的和有希望的机会。这些效应与内源性抗肿瘤免疫反应和免疫原性细胞死亡有关，同时冷免疫肿瘤转化为热肿瘤。最后，在一组膀胱癌患者中，增加的 G9a 表达与对程序性细胞死亡蛋白 1 抑制的抗性有关。总之，这些发现支持使用表观遗传抑制剂和免疫检查点阻断的组合治疗膀胱癌的新的和有希望的机会。这些效应与内源性抗肿瘤免疫反应和免疫原性细胞死亡有关，同时冷免疫肿瘤转化为热肿瘤。最后，在一组膀胱癌患者中，增加的 G9a 表达与对程序性细胞死亡蛋白 1 抑制的抗性有关。总之，这些发现支持使用表观遗传抑制剂和免疫检查点阻断的组合治疗膀胱癌的新的和有希望的机会。

更新日期：2019-07-04

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