Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.
Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland.
Nat Immunol. 2019 Feb;20(2):206-217. doi: 10.1038/s41590-018-0290-0. Epub 2019 Jan 21.
Immune checkpoint blockade therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to insufficient T cell infiltration in tumors. Here we show that expression of mitochondrial uncoupling protein 2 (UCP2) in tumor cells determines the immunostimulatory feature of the tumor microenvironment (TME) and is positively associated with prolonged survival. UCP2 reprograms the immune state of the TME by altering its cytokine milieu in an interferon regulatory factor 5-dependent manner. Consequently, UCP2 boosts the conventional type 1 dendritic cell- and CD8 T cell-dependent anti-tumor immune cycle and normalizes the tumor vasculature. Finally we show, using either a genetic or pharmacological approach, that induction of UCP2 sensitizes melanomas to programmed cell death protein-1 blockade treatment and elicits effective anti-tumor responses. Together, this study demonstrates that targeting the UCP2 pathway is a potent strategy for alleviating the immunosuppressive TME and overcoming the primary resistance of programmed cell death protein-1 blockade.
免疫检查点阻断疗法改变了癌症治疗的模式。然而，由于肿瘤中 T 细胞浸润不足，大多数患者缺乏有效的反应。在这里，我们表明肿瘤细胞中线粒体解偶联蛋白 2 (UCP2) 的表达决定了肿瘤微环境 (TME) 的免疫刺激特征，并与延长的生存时间呈正相关。UCP2 通过干扰素调节因子 5 依赖的方式改变其细胞因子环境，重新编程 TME 的免疫状态。因此，UCP2 增强了传统的 1 型树突状细胞和 CD8 T 细胞依赖性抗肿瘤免疫循环，并使肿瘤血管正常化。最后，我们使用遗传或药理学方法表明，诱导 UCP2 使黑色素瘤对程序性细胞死亡蛋白-1 阻断治疗敏感，并引发有效的抗肿瘤反应。总之，这项研究表明，靶向 UCP2 途径是缓解免疫抑制性 TME 和克服程序性细胞死亡蛋白-1 阻断的主要耐药性的有效策略。
