The Drug Development Unit, The Institute of Cancer Research and The Royal Marsden Hospital, Sutton, United Kingdom.
Breast Unit, The Royal Marsden Hospital, London, United Kingdom.
Clin Cancer Res. 2019 Jan 1;25(1):21-28. doi: 10.1158/1078-0432.CCR-18-1999. Epub 2018 Sep 17.
Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor-positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.
细胞分裂失调导致异常细胞增殖是癌症的一个关键特征，因此成为创新抗癌药物开发的合理且重要的靶点。三种选择性细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂已获得美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准，用于治疗激素受体阳性/HER2 阴性晚期乳腺癌。一个主要的新认识是，这些抑制剂不仅具有细胞抑制作用，而且在肿瘤细胞与宿主免疫反应的相互作用中发挥关键作用。然而，要引发有效的免疫反应，淋巴细胞也必须增殖。本综述旨在综合我们对 CDK4/6 抑制剂在细胞周期控制中的作用的最新认识，以及它们对 T 细胞和其他关键免疫细胞的生物学影响，以及这些药物增强抗癌免疫的临床前证据的融合。我们旨在为理解细胞周期在抗癌免疫中的作用提供一个框架，讨论正在进行的临床试验评估这一概念以及与免疫疗法联合应用的挑战。
