摘要
目的探讨白细胞介素33(IL-33)联合免疫检查点抑制剂(ICIs)在黑色素瘤治疗中的作用及机制。方法选用小鼠B16黑色素瘤细胞株构建IL-33过表达(B16-IL-33)细胞模型,在C57BL/6J小鼠皮下接种B16-Vec及B16-IL-33细胞构建荷瘤模型,探讨IL-33联合ICIs的抗肿瘤作用及疗效。流式细胞术检测并分析不同治疗组别肿瘤浸润调节性T细胞(Treg)数量及表型差异。结果接种B16-IL-33的荷瘤小鼠肿瘤生长速度慢于B16-Vec小鼠(t=6.708,P<0.001),总生存期延长(χ^(2)=21.941,P<0.001),差异均有统计学意义。肿瘤微环境中,B16-IL-33组肿瘤浸润Treg细胞(t=9.149,P<0.001)、驻留CD103^(+)Treg细胞(t=7.568,P<0.001)和活化Treg细胞(CD39^(+)Treg:t=8.443,P<0.001;Helios^(+)Treg:t=8.891,P<0.001;CD39^(+)Helios^(+)Treg:t=11.351,P<0.001)比率均高于B16-Vec组。IL-33联合ICIs治疗,可减少肿瘤微环境中浸润Treg比率,与治疗前B16-IL-33荷瘤小鼠[(23.43±4.20)%]肿瘤浸润Treg细胞比例相比,PD-1单抗治疗后B16-IL-33荷瘤小鼠Treg细胞比例降低,为(10.40±3.20)%,t=4.274,P=0.003;CTLA-4单抗治疗后Treg细胞比例也降低,为(14.48±2.38)%,t=3.211,P=0.009。结论IL-33在黑色素瘤肿瘤细胞中过表达可抑制肿瘤生长并延长荷瘤小鼠生存期,IL-33联合ICIs可协同增效治疗黑色素瘤,具有潜在的临床应用价值。
Objective To investigate the effect and mechanism of interleukin-33(IL-33)combined with immunocheckpoint inhibitors(ICIs)in the treatment of melanoma.Methods The mouse B16 melanoma cell line was selected to construct the IL-33 overexpression(B16-IL-33)cell model,and the C57 BL/6 J mice were subcutaneously inoculated with B16-Vec and B16-IL-33 cells to construct the tumor bearing model.The anti-tumor effect and efficacy of IL-33 combined with ICIs were discussed.Flow cytometry was used to detect and analyze the number and phenotype difference of tumor invasion regulatory T cells(Treg)in different treatment groups.Results The tumor growth rate of tumor bearing mice inoculated with B16-IL-33 was slower than that of B16-Vec mice(t=6.708,P<0.001),and the total survival period was prolonged(χ^(2)=21.941,P<0.001).In tumor microenvironment,the ratios of tumor infiltrating Treg cells(t=9.149,P<0.001),resident CD103^(+)Treg cells(t=7.568,P<0.001)and activated Treg cells(CD39+Treg:t=8.443,P<0.001;Helios^(+)Treg:t=8.891,P<0.001;CD39+Helios^(+)Treg:t=11.351,P<0.001)in B16-IL-33 group were higher than those in B16-Vec group.IL-33 combined with ICIs treatment can reduce the ratio of Treg cells infiltrating into the tumor microenvironment.Compared with the ratio of Treg cells infiltrating into B16-IL-33 tumor bearing mice[(23.43±4.20)%]before treatment,the ratio of Treg cells infiltrating into B16-IL-33 tumor bearing mice after PD-1 monoclonal antibody treatment decreased to(10.40±3.20)%,t=4.274,P=0.003.After treatment with CTLA-4 monoclonal antibody,the ratio of Treg cells also decreased,which was(14.48±2.38)%,t=3.211,P=0.009.Conclusion Overexpression of IL-33in melanoma tumor cells can inhibit tumor growth and prolong the survival period of tumor bearing mice.IL-33combined with ICIs can synergistically treat melanoma,which has potential clinical application value.
作者
孙润孜
李源
黄浩
澹博
徐斌
郑晓
陈陆俊
SUN Run-zi;LI Yuan;HUANG Hao;TAN Bo;XU Bin;ZHENG Xiao;CHEN Lu-jun(Third Affiliated Hospital of Soochow University,Changzhou213003,China)
出处
《中华肿瘤防治杂志》
CAS
北大核心
2022年第22期1585-1591,共7页
Chinese Journal of Cancer Prevention and Treatment
基金
国家自然科学基金(82172689,81902386)
江苏省自然科学基金(BK20211065)
中国博士后科学基金面上项目(2021M700543,2021M700547)
江苏省“六个一”拔尖人才项目(LGY2020034)
常州市国际合作项目(CZ20210035)
常州市应用基础研究计划(CJ20190094,CJ20210121)。
