細(xì)胞周期蛋白依賴型激酶4和6（CDK4/6）是細(xì)胞分裂增殖周期（G1期→S期→G2期→M期）的關(guān)鍵調(diào)節(jié)蛋白，為各種惡性腫瘤細(xì)胞形成和生長所必需。CDK4/6抑制劑對多種實體腫瘤表現(xiàn)出顯著活性，其主要作用機(jī)制被認(rèn)為是抑制視網(wǎng)膜母細(xì)胞瘤基因（一種抑癌基因）抑制因子磷酸化，簡而言之即抑制對抑癌基因的抑制作用，使腫瘤細(xì)胞停滯于細(xì)胞周期的G1期。既往認(rèn)為，由于CDK4/6抑制劑可能影響T淋巴細(xì)胞增殖，故可抑制抗腫瘤免疫反應(yīng)，但是最新研究結(jié)果恰恰相反。
2017年8月16日，英國《自然》在線發(fā)表美國哈佛大學(xué)醫(yī)學(xué)院、達(dá)納法伯癌癥研究所、布列根醫(yī)院和波士頓婦女醫(yī)院、圣路易斯華盛頓大學(xué)醫(yī)學(xué)院、貝勒醫(yī)學(xué)院、哈佛大學(xué)和麻省理工學(xué)院布羅德研究所的研究報告，發(fā)現(xiàn)CDK4/6抑制劑不僅可使乳腺癌細(xì)胞停止分裂增殖，還可觸發(fā)抗腫瘤免疫反應(yīng)，刺激免疫系統(tǒng)攻擊并殺死乳腺癌細(xì)胞，與其他免疫療法聯(lián)合使用時抗癌效果可能更大，該新發(fā)現(xiàn)打開了CDK4/6抑制劑聯(lián)合免疫療法的大門。
首先，該研究利用乳腺癌和其他實體瘤小鼠模型，發(fā)現(xiàn)選擇性CDK4/6抑制劑阿本昔布不僅誘導(dǎo)腫瘤細(xì)胞周期停滯，而且還促進(jìn)抗腫瘤免疫。
隨后，該研究利用選擇性CDK4/6抑制劑帕泊昔布＋阿那曲唑新輔助治療雌激素受體陽性乳腺癌患者臨床研究（NeoPalAna）連續(xù)活檢標(biāo)本進(jìn)行轉(zhuǎn)錄分析，證實上述現(xiàn)象。
研究發(fā)現(xiàn)，CDK4/6抑制劑主要通過兩個方面增強(qiáng)抗腫瘤免疫反應(yīng)：
第一，激活殺傷性T淋巴細(xì)胞：CDK4/6抑制劑可激活腫瘤細(xì)胞表達(dá)內(nèi)源性逆轉(zhuǎn)錄病毒元素，從而增加細(xì)胞內(nèi)雙鏈RNA水平，反過來刺激III型干擾素（IFNλ）產(chǎn)生，從而增強(qiáng)腫瘤抗原呈遞，供細(xì)胞毒性T淋巴細(xì)胞識別。
第二，減少調(diào)節(jié)性T淋巴細(xì)胞：CDK4/6抑制劑可顯著抑制調(diào)節(jié)性T淋巴細(xì)胞的增殖。調(diào)節(jié)性T淋巴細(xì)胞是一類具有負(fù)調(diào)節(jié)作用的T淋巴細(xì)胞亞群，可抑制免疫反應(yīng)。調(diào)節(jié)性T細(xì)胞減少，意味著免疫系統(tǒng)的攻擊力更為激烈。
此外，CDK4/6抑制劑對腫瘤細(xì)胞和調(diào)節(jié)性T淋巴細(xì)胞的影響，還可引起DNA甲基轉(zhuǎn)移酶活性降低。DNA甲基轉(zhuǎn)移酶是催化DNA堿基甲基化作用的酶，甲基化作用一般發(fā)生在DNA合成之后，是轉(zhuǎn)錄因子E2F的靶標(biāo)，對控制細(xì)胞周期及抑癌基因功能起到重要作用，
最終，這些事件促進(jìn)細(xì)胞毒性T淋巴細(xì)胞介導(dǎo)的腫瘤細(xì)胞清除，并可進(jìn)一步被免疫檢查點抑制劑加強(qiáng)，減少腫瘤細(xì)胞的免疫逃逸。這些環(huán)環(huán)相扣的疊加效應(yīng)，最終導(dǎo)致乳腺癌細(xì)胞生長的停止或逆轉(zhuǎn)。
因此，該研究結(jié)果表明，CDK4/6抑制劑可增強(qiáng)腫瘤免疫原性，誘導(dǎo)機(jī)體產(chǎn)生免疫反應(yīng)，并為CDK4/6抑制劑＋免疫檢查點抑制劑的新聯(lián)合方案進(jìn)行抗癌治療提供依據(jù)。
相關(guān)閱讀
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
