PRKCH的表达对CD8^(+)T细胞功能及黑色素瘤免疫治疗的影响  

Effects of PRKCH on CD8^(+)T cell function and melanoma immunotherapy

作　　者：余忍忍 吕浩 储涵 金铮 贾罄竹 陈德高 朱波[1,2,5] YU Renren;LYU Hao;CHU Han;JIN Zheng;JIA Qingzhu;CHEN Degao;ZHU Bo(Department of Oncology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang Province,325000;Department of Oncology,Second Affiliated Hospital,Army Medical University(Third Military Medical University),Chongqing,400037;Center of Growth,Metabolism and Aging,College of Life Sciences,Sichuan University,Chengdu,Sichuan Province,610064;Glorious Med Clinical Laboratory Co.,Ltd,Shanghai,201318;Chongqing Key Laboratory of Immunotherapy,Chongqing,400037,China)

机构地区：[1]温州医科大学附属第一医院肿瘤科,浙江温州325000 [2]陆军军医大学(第三军医大学)第二附属医院肿瘤科,重庆400037 [3]四川大学生命科学学院生长代谢衰老研究中心,成都610064 [4]上海仁东医学检验所有限公司,上海201318 [5]肿瘤免疫治疗重庆市重点实验室,重庆400037

出　　处：《陆军军医大学学报》2024年第6期556-566,共11页Journal of Army Medical University

基　　金：国家杰出青年科学基金资助项目(81925030)。

摘　　要：目的 探讨PRKCH表达对CD8^(+)T细胞功能的影响及其在黑色素瘤免疫治疗效果预测中的作用。方法 运用Kaplan-Meier法分析黑色素瘤免疫治疗队列以及肿瘤基因组图谱(TCGA)数据中PRKCH在黑色素瘤中的表达及其与总生存期(overall survival, OS)的相关性。利用单细胞RNA测序(single-cell RNA-sequencing, scRNA-seq)数据分析PRKCH的细胞表达群体,利用蛋白质互作网络(protein-protein interaction networks, PPI)和基因集富集分析(gene set enrichment analysis, GSEA)评估PRKCH诱导抗肿瘤免疫应答的机制。利用逆转录病毒过表达和敲减PRKCH,检测小鼠CD8^(+)T细胞功能。利用B16-OVA小鼠黑色素瘤模型验证PRKCH过表达的OT-1 CD8^(+)T细胞对肿瘤生长的影响。结果 在黑色素瘤免疫治疗队列和TCGA数据中,高水平的PRKCH显著延长患者OS(P<0.05)。scRNA-seq分析显示PRKCH可以在T细胞表达。PPI、GSEA和scRNA-seq分析显示PRKCH的高表达与更多的细胞毒性和记忆性T细胞形成相关。过表达和敲减PRKCH分别增强和减少CD8^(+)T细胞的增殖及IFN-γ、Granzyme B的表达。过表达PRKCH增强OT-1 CD8^(+)T细胞的肿瘤抑制能力。结论 PRKCH增强CD8^(+)T细胞抑制肿瘤进展的能力,并可以用于预测黑色素瘤免疫治疗效果。Objective To explore the effect of PRKCH on CD8^(+)T cell function and its role in predicting the efficacy of melanoma immunotherapy.Methods Kaplan-Meier survival analysis was used to evaluate the correlation between PRKCH and overall survival(OS)in melanoma immunotherapy cohorts and The Cancer Genome Atlas(TCGA)data.Single-cell RNA-sequencing(scRNA-seq)data were employed to analyze the cellular expression of PRKCH.Protein-protein interaction(PPI)networks and gene set enrichment analysis(GSEA)were applied to analyze the mechanism of PRKCH-induced anti-tumor immune responses.After retroviral overexpression and knockdown of PRKCH,the function of mouse CD8^(+)T cells was examined.The anti-tumor effect of PRKCH overexpressed OT-1 CD8+T cells was assessed using B16-OVA mouse melanoma model.Results A positive correlation was observed between PRKCH expression and OS in the melanoma ICI cohorts and SKCM data in TCGA.scRNA-seq data indicated that PRKCH was expressed in T cells.PPI,GSEA and scRNA-seq data showed that PRKCH may induce more cytotoxic and memory T cells.PRKCH overexpression and knockdown enhanced and decreased CD8^(+)T cell proliferation and IFN-γand Granzyme B expression,respectively.Additionally,PRKCH overexpression enhanced the tumor inhibition of OT-1 CD8^(+)T cells.Conclusion PRKCH enhances the anti-tumor effect of CD8^(+)T cells,and can be used to predict the efficacy of immunotherapy in melanoma.

关 键 词：PRKCH 黑色素瘤 免疫治疗 肿瘤微环境 CD8^(+)T细胞 

分 类 号：R394.3[医药卫生—医学遗传学] R730.51[医药卫生—基础医学] R739.5