Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea.
Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul, Korea.
Cancer Res. 2018 May 15;78(10):2638-2653. doi: 10.1158/0008-5472.CAN-17-2325. Epub 2018 Feb 6.
Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOG cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3 immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3 immune-refractory cancer. These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3 immune-refractroy cancer. .
肿瘤免疫引起的免疫编辑促使肿瘤细胞获得难治性表型。我们之前曾证明，肿瘤抗原特异性 T 细胞通过编辑这些细胞，使它们对 CTL 杀伤产生抗性，并富集 NANOG 癌症干细胞样细胞。在这项研究中，我们表明联会复合体蛋白 3（SCP3），Cor1 家族的成员，在免疫编辑细胞中过度表达，并通过超激活细胞周期蛋白 D1-CDK4/6 轴来上调 NANOG。SCP3-细胞周期蛋白 D1-CDK4/6 轴在各种类型的人类癌症中都得到了保留，并且与宫颈癌患者的无进展生存期呈负相关。用抑制剂 palbociclib 靶向 CDK4/6 可逆转 SCP3 免疫编辑肿瘤细胞的多侵袭表型，并可长期控制疾病。总的来说，我们的研究结果确立了 SCP3、NANOG、细胞周期蛋白 D1 和 CDK4/6 之间多侵袭性的牢固分子联系，并确定 CDK4/6 抑制剂是控制 SCP3 免疫难治性癌症的有效药物。这些发现揭示了细胞周期蛋白 D1-CDK4/6 抑制作为控制 SCP3 免疫难治性癌症的有效策略。
