CDK4/6抑制劑 非僅抗癌藥 ~免疫調節功能!

CDK4/6 inhibition triggers anti-tumour immunity Nature 548, 471–475 (24 August 2017) 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 malignancies1, 2. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours3, 4. 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 cells5. 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.

CDK4/6抑制劑的抗腫瘤效果 Nature 548, 7668 發表日期： 2017年8月24日目前，CDK4/6抑制劑在臨床試驗中被用於治療乳腺癌，已知它們會誘導細胞抑制。在本文中，作者發現了CDK4/6抑制劑的一種新型效應，可能有助於增強其治療效果。通過增加腫瘤細胞抗原呈遞，同時抑制調節性T細胞的增殖，CDK4/6抑制劑可以增強抗腫瘤免疫性。之所以會產生這些效果與治療後DNMT1的表達減少有關。在體內，將CDK4/6抑制劑與檢查點阻斷結合起來，可以增強抗腫瘤效果。