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细胞周期蛋白依赖型激酶4和6（CDK4/6）是细胞分裂增殖周期（G1期→S期→G2期→M期）的关键调节蛋白，为各种恶性肿瘤细胞形成和生长所必需。CDK4/6抑制剂对多种实体肿瘤表现出显著活性，其主要作用机制被认为是抑制视网膜母细胞瘤基因（一种抑癌基因）抑制因子磷酸化，简而言之即抑制对抑癌基因的抑制作用，使肿瘤细胞停滞于细胞周期的G1期。既往认为，由于CDK4/6抑制剂可能影响T淋巴细胞增殖，故可抑制抗肿瘤免疫反应，但是最新研究结果恰恰相反。 2017年8月16日，英国《自然》在线发表美国哈佛大学医学院、达纳法伯癌症研究所、布列根医院和波士顿妇女医院、圣路易斯华盛顿大学医学院、贝勒医学院、哈佛大学和麻省理工学院布罗德研究所的研究报告，发现CDK4/6抑制剂不仅可使乳腺癌细胞停止分裂增殖，还可触发抗肿瘤免疫反应，刺激免疫系统攻击并杀死乳腺癌细胞，与其他免疫疗法联合使用时抗癌效果可能更大，该新发现打开了CDK4/6抑制剂联合免疫疗法的大门。 首先，该研究利用乳腺癌和其他实体瘤小鼠模型，发现选择性CDK4/6抑制剂阿本昔布不仅诱导肿瘤细胞周期停滞，而且还促进抗肿瘤免疫。 随后，该研究利用选择性CDK4/6抑制剂帕泊昔布＋阿那曲唑新辅助治疗雌激素受体阳性乳腺癌患者临床研究（NeoPalAna）连续活检标本进行转录分析，证实上述现象。 研究发现，CDK4/6抑制剂主要通过两个方面增强抗肿瘤免疫反应： 第一，激活杀伤性T淋巴细胞：CDK4/6抑制剂可激活肿瘤细胞表达内源性逆转录病毒元素，从而增加细胞内双链RNA水平，反过来刺激III型干扰素（IFNλ）产生，从而增强肿瘤抗原呈递，供细胞毒性T淋巴细胞识别。 第二，减少调节性T淋巴细胞：CDK4/6抑制剂可显著抑制调节性T淋巴细胞的增殖。调节性T淋巴细胞是一类具有负调节作用的T淋巴细胞亚群，可抑制免疫反应。调节性T细胞减少，意味着免疫系统的攻击力更为激烈。 此外，CDK4/6抑制剂对肿瘤细胞和调节性T淋巴细胞的影响，还可引起DNA甲基转移酶活性降低。DNA甲基转移酶是催化DNA碱基甲基化作用的酶，甲基化作用一般发生在DNA合成之后，是转录因子E2F的靶标，对控制细胞周期及抑癌基因功能起到重要作用， 最终，这些事件促进细胞毒性T淋巴细胞介导的肿瘤细胞清除，并可进一步被免疫检查点抑制剂加强，减少肿瘤细胞的免疫逃逸。这些环环相扣的叠加效应，最终导致乳腺癌细胞生长的停止或逆转。 因此，该研究结果表明，CDK4/6抑制剂可增强肿瘤免疫原性，诱导机体产生免疫反应，并为CDK4/6抑制剂＋免疫检查点抑制剂的新联合方案进行抗癌治疗提供依据。 相关阅读 Nature. 2017 Aug 16. [Epub ahead of print] CDK4/6 inhibition triggers anti-tumour immunity. Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA; Washington University School of Medicine, St. Louis, Missouri, USA; Baylor College of Medicine, Houston, Texas, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment. PMID: 28813415 DOI: 10.1038/nature23465 |
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