摘要
目的探讨周期蛋白依赖性激酶(CDK2)对小鼠神经母细胞瘤免疫微环境的影响。方法评估CDK2抑制剂PF-07104091对皮下MYCN阴性神经母细胞瘤细胞SH-EP在C57BL/6N WT小鼠体内肿瘤生长的影响。评估CDK2稳定敲低MYCN的阴性神经母细胞瘤细胞在C57BL/6N WT小鼠体内的成瘤能力。评估CDK2抑制剂或者敲低CDK2对MYCN阴性神经母细胞瘤细胞增殖水平和凋亡水平的影响。探索CDK2抑制剂或者敲低CDK2是否影响MYCN阴性神经母细胞瘤免疫微环境。结果PF-07104091显著抑制MYCN阴性神经母细胞瘤生长并增加小鼠总生存率。CDK2敲低能够显著抑制肿瘤生长并增加小鼠总生存率。CDK2抑制剂或者敲低CDK2并不影响MYCN阴性神经母细胞瘤细胞的增殖水平和凋亡水平。CDK2抑制剂或者敲低CDK2的MYCN阴性神经母细胞瘤中观察到的CD3+T细胞、CD4^(+)T细胞、CD8^(+)T细胞和DC细胞的比例显著升高。CDK2抑制剂处理或者敲低CDK2后,MYCN阴性神经母细胞瘤中IFN-γ的水平上升,并且IFN-γ通路中的关键基因IFNB1、STAT1、TLR3、DDX58、CCL17、TAP1、TX2表达上调。腹腔注射或不注射CDK2抑制剂PF-07104091并不影响IFNGR1^(-/-)小鼠的生长速度和生存率。敲低与未敲低CDK2的MYCN阴性神经母细胞瘤在IFNGR1^(-/-)小鼠身上生长肿瘤的速度相似并且生存率相似。结论CDK2通过IFN-γ通路影响肿瘤免疫微环境中CD3+T细胞、CD4^(+)T细胞、CD8^(+)T细胞和DC细胞的比例。
Neuroblastoma is one of the most common extracranial solid tumors in children,accounting for 15%of pediatric cancer-related deaths.CDK2 silencing leads to apoptosis in MYCN positive neuroblastoma,but not in MYCN negative neuroblastoma.However,little is known about whether cyclin dependent kinase 2(CDK2)inhibits MYCN negative neuroblastoma tumorigenesis and its effect on tumor immune microenvironment.In this study,we evaluated the effect of CDK2 inhibitor PF-07104091 or CDK2 stable knockdown on the tumor growth of subcutaneous MYCN negative neuroblastoma cells SH-EP in C57BL/6N WT mice,so as to explore whether CDK2 inhibitors or knockdown of CDK2 affect the immune microenvironment of MYCN negative neuroblastoma.Data showed that both PF-07104091 and CDK2 knockdown significantly inhibited the growth of MYCN negative neuroblastoma and increased murine overall survival of mice;CDK2 inhibitors or CDK2 knockdown did not affect the proliferation or apoptosis of MYCN negative neuroblastoma cells.PF-07104091 and CDK2 knockdown groups demonstrated significant increase in the percentages of CD3+T cells,CD4^(+)T cells,CD8^(+)T cells,and DC cells.After CDK2 inhibitors or CDK2 knockdown treatment,the level of IFN-γin MYCN negative neuroblastoma increased,and the expressions of the key genes of IFN-γpathway IFNB1,STAT1,TLR3,DDX58,CCL17,TAP1,TX2 were up-regulated.Intraperitoneal injection of CDK2 inhibitor PF-07104091 did not affect the growth rate and survival rate of IFNGR1^(-/-)mice;MYCN negative neuroblastoma with or without CDK2 knockdown had similar tumor growth rates and survival rates in IFNGR1^(-/-)mice.
作者
许雅丽
李笃妙
吴强
林俊山
XU Yali;LI Dumiao;WU Qiang;LIN Junshan(Department of Pediatric Surgery,First Affiliated Hospital of Fujian Medical University,Fuzhou 350005,China)
出处
《免疫学杂志》
CAS
CSCD
北大核心
2023年第5期379-387,共9页
Immunological Journal
基金
福建省自然科学基金(2019J01433)。
