首页|c-Met作为嵌合抗原受体T(CAR-T)细胞治疗结肠癌靶点的生物信息学预测及验证

c-Met作为嵌合抗原受体T(CAR-T)细胞治疗结肠癌靶点的生物信息学预测及验证

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目的 探索细胞间充质上皮转化因子(c-Met)作为嵌合抗原受体T(CAR-T)细胞治疗结肠癌有效靶点的可能性。方法 通过生物信息学方法分析c-Met在结肠腺癌(COAD)中的特异性表达及其临床意义;使用免疫组织化学验证结肠癌临床患者肿瘤组织中c-Met的表达，采用流式细胞术检测HCT116结肠癌细胞株中c-Met的表达;使用慢病毒感染人外周血单个核细胞(PBMC)中原代T细胞，制备靶向c-Met的二代CAR-T细胞，并观察c-Met CAR-T细胞对HCT116细胞的抑制效果。结果 免疫组织化学与生物信息学显示c-Met在COAD中高表达，其中相对低表达的患者生存预后较好，在正常结肠组织中低表达或不表达。流式细胞术显示c-Met在HCT116细胞中也高表达。c-Met CAR-T细胞能够靶向表达抗原的肿瘤细胞，并且在抗原刺激下，CAR-T细胞特异性增殖，起到杀伤癌细胞与释放白细胞介素2(IL-2)和γ干扰素(IFN-γ)的生物学作用。结论 c-Met有成为COAD潜在治疗靶点的潜能;c-Met CAR-T细胞在体外对结肠癌细胞具有抑制作用。
Bioinformatic prediction and validation of cellular-mesenchymal epithelial transition(c-Met)as a target for chimeric antigen receptor T(CAR-T)cell therapy in the treatment of colorectal cancer
Objective To explore the potential of the cell surface receptor c-Met as an effective target for chimeric antigen receptor T-cell(CAR-T)therapy in colorectal cancer.Methods The bioinformatics was used to analyze the specific expression of c-Met in colorectal adenocarcinoma(COAD)and its clinical significance.c-Met protein expression was detected by immunohistochemistry in tumor tissues obtained from colorectal cancer patients.Flow cytometry was utilized to assess the expression of c-Met in the HCT116 human colorectal cancer cell line.Additionally,primary T cells isolated from human peripheral blood mononuclear cells(PBMCs)were transduced with a lentivirus to generate second-generation CAR-T cells targeting c-Met,followed by an observation of the inhibitory effects of these c-Met-targeted CAR-T cells on HCT116 cells.Results Immunohistochemistry and bioinformatics data both demonstrated that c-Met was over-expressed in COAD,with patients exhibiting relatively lower expression showing better prognosis.In normal colonic tissue,c-Met was either expressed at low levels or not expressed.Flow cytometry revealed high expression of c-Met in HCT116 cells as well.The c-Met-targeted CAR-T cells were capable of specifically recognizing and targeting antigen-expressing tumor cells.CAR-T cells proliferated specifically under antigenic stimulation,exerting cytotoxic effects on cancer cells and releasing cytokines interleukin 2(IL-2)and interferon-gamma(IFN-γ),thereby demonstrating the biological functions.Conclusion c-Met may be a promising therapeutic target in COAD;c-Met-targeted CAR-T cells demonstrate inhibitory effects on colorectal cancer cells in vitro.

chimeric antigen receptor T(CAR-T)cellscolorectal adenocarcinoma(COAD)cellular-mesenchymal epithelial transition(c-Met)bioinformatics

彭上、闵静婷、龙赤荣、谢梓龙、张露、李海鹏、李正红

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蚌埠医科大学心血管疾病基础与临床重点实验室,安徽蚌埠 233030

蚌埠医科大学生理学教研室,安徽蚌埠 233030

嵌合抗原受体T(CAR-T)细胞 结肠腺癌(COAD) 细胞间充质上皮转化因子(c-Met) 生物信息学

国家自然科学基金安徽省教育厅高校科研重点项目安徽省高校自然科学研究重大项目蚌埠医学院自然科学项目蚌埠医科大学研究生创新项目国家级大学生创新创业项目国家级大学生创新创业项目

814726562023AH0519912022AH0402242021byzd015Byycx22015202210367037202110367001

2024

10.13423/j.cnki.cjcmi.009780

细胞与分子免疫学杂志
中国免疫学会,第四军医大学

细胞与分子免疫学杂志

CSTPCD北大核心
影响因子：0.817
ISSN：1007-8738
年,卷(期)：2024.40(7)