Expression and significance of CCR8 on tumor⁃infiltrating Treg cells in ovarian cancer
Author:
Affiliation:
Fund Project:
摘要
|
图/表
|
访问统计
|
参考文献
|
相似文献
|
引证文献
|
资源附件
|
文章评论
摘要:
目的:分析趋化因子受体8(C-C motif chemokine receptor 8,CCR8)在卵巢癌肿瘤浸润性调节性 T 细胞(regulatory T cell,Treg)中的表达,探讨CCR8对Treg分化的作用。方法:构建C57BL/6小鼠卵巢癌细胞ID8荷瘤模型;流式细胞术检测小鼠肿瘤组织、脾脏和外周血中Treg上CCR8的表达比例,CCR8+ Treg上免疫检查点相关蛋白程序性细胞死亡蛋白1(programmed cell death protein 1,PD-1)、细胞素性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4,CTLA-4)、可诱导的T细胞共刺激分子 (inducible T cell costimulators,ICOS)、淋巴细胞激活基因3(lymphocyte activation gene 3,LAG-3)的表达;流式细胞术检测CCR8 变构抑制剂AZ084加入前后对C57BL/6小鼠脾脏中初始CD4+ T细胞向Treg分化的影响。结果:卵巢癌荷瘤小鼠肿瘤中Treg上的CCR8表达相比脾脏、外周血的Treg显著增高;相比CCR8- Treg,CCR8+ Treg上免疫检查点相关蛋白表达更高;AZ084有效抑制小鼠脾脏中初始CD4+ T细胞向Treg的分化。结论:CCR8+ Treg在肿瘤浸润性Treg中占主要比例,CCR8作为卵巢癌浸润性 Treg的主要标志物,变构CCR8蛋白可以抑制Treg的分化。靶向消除CCR8+ Treg可为改善卵巢癌肿瘤微环境的免疫抑制状态提供新思路。
Abstract:
Objective:To analyze the expression of C-C motif chemokine receptor 8(CCR8)in tumor-infiltrating regulatory T(Treg) cells in ovarian cancer and to investigate the role of CCR8 in Treg cell differentiation. Methods:An ID8 ovarian cancer cell-bearing model was established in C57BL/6 mice. The flow cytometry was used to detect the expression proportion of CCR8 on Treg in mouse tumor tissues,spleens and peripheral blood,and the expression levels of programmed cell death protein 1(PD-1),cytotoxic T-lymphocyte antigen 4(CTLA-4),inducible T-cell costimulator(ICOS)and lymphocyte-activation gene 3(LAG-3)on CCR8+ Treg cells. The flow cytometry was also used to detect the changes in the differentiation ratio of naive CD4+ T cells to Treg cells in the spleens of C57BL/6 mice before and after the addition of the CCR8 conformational inhibitor AZ084. Results:The expression of CCR8 on Treg cells in the tumors of ovarian cancer -bearing mice was significantly higher,compared with that in the spleens and peripheral blood. Compared with CCR8- Treg cells,CCR8 + Treg cells also had a higher expression of immune checkpoint related proteins. AZ084 effectively inhibited the differentiation of naive CD4 + T cells into Treg cells in the mouse spleens. Conclusion:CCR8 + Treg cells constitute the major proportion of tumor-infiltrating Treg cells,and CCR8 acts as a primary marker of ovarian cancer-infiltrating Treg cells. Conformational modulation of the CCR8 protein can inhibit the differentiation ratio of Treg cells. The targeted elimination of CCR8+ Treg cells may provide new insights for improving the immunosuppressive state of tumor microenvironment in ovarian cancer.