Korpal Manav, Puyang Xiaoling, Jeremy Wu Zhenhua, Seiler Roland, Furman Craig, Oo Htoo Zarni, Seiler Michael, Irwin Sean, Subramanian Vanitha, Julie Joshi Jaya, Wang Chris K, Rimkunas Victoria, Tortora Davide, Yang Hua, Kumar Namita, Kuznetsov Galina, Matijevic Mark, Chow Jesse, Kumar Pavan, Zou Jian, Feala Jacob, Corson Laura, Henry Ryan, Selvaraj Anand, Davis Allison, Bloudoff Kristjan, Douglas James, Kiss Bernhard, Roberts Morgan, Fazli Ladan, Black Peter C, Fekkes Peter, Smith Peter G, Warmuth Markus, Yu Lihua, Hao Ming-Hong, Larsen Nicholas, Daugaard Mads, Zhu Ping
H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA, 02139, USA.
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada, V5Z 1M9.
Nat Commun. 2017 Jul 24;8(1):103. doi: 10.1038/s41467-017-00147-w.
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ/RXRα impairs CD8 T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.
肌层浸润性膀胱癌（MIBC）是一种侵袭性疾病，治疗选择有限。尽管免疫疗法已被批准用于治疗MIBC，但大多数患者无反应，这表明存在互补的免疫逃逸机制。在此，我们报告PPARγ/RXRα信号通路构成了MIBC免疫逃逸的肿瘤内在机制。RXRα丝氨酸427（S427F/Y）位点的反复突变，通过PPARγ/RXRα异二聚体的构象激活，以及PPARγ的局灶性扩增/过表达，共同调节PPARγ/RXRα依赖性转录程序。免疫细胞浸润受激活的PPARγ/RXRα控制，其抑制炎性细胞因子的表达/分泌。临床数据集和体内肿瘤模型表明，PPARγ/RXRα损害CD8 T细胞浸润，并赋予对免疫疗法的部分抗性。敲低PPARγ或RXRα以及对PPARγ的药理学抑制显著增加细胞因子表达，提示恢复免疫监视和对免疫疗法敏感性的治疗方法。我们的研究揭示了一类调节癌症免疫微环境的肿瘤细胞内在“免疫癌基因”。肌层浸润性膀胱癌（MIBC）是一种潜在致命性疾病。本文作者描述了MIBC中多种基因改变，这些改变共同导致PPARγ/RXRα的组成性激活，并通过抑制CD8+ T细胞募集导致免疫监视逃逸。
