[1]刘裕琳),张 震),曹 玲),等.食管癌组织中IDO1的表达及犬尿酸对间皮素CAR-T细胞功能的影响[J].郑州大学学报(医学版),2019,(03):344-348.[doi:10.13705/j.issn.1671-6825.2019.02.042]
 LIU Yulin),ZHANG Zhen),CAO Ling),et al.Expression of IDO1 and effects of kynurenine on the function of mesothelin-CAR-T cells[J].JOURNAL OF ZHENGZHOU UNIVERSITY(MEDICAL SCIENCES),2019,(03):344-348.[doi:10.13705/j.issn.1671-6825.2019.02.042]
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食管癌组织中IDO1的表达及犬尿酸对间皮素CAR-T细胞功能的影响()
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《郑州大学学报(医学版)》[ISSN:1671-6825/CN:41-1340/R]

卷:
期数:
2019年03期
页码:
344-348
栏目:
系列研究
出版日期:
2019-05-20

文章信息/Info

Title:
Expression of IDO1 and effects of kynurenine on the function of mesothelin-CAR-T cells
作者:
刘裕琳123)张 震13)曹 玲14)申春一123)张 毅1235)
1)郑州大学第一附属医院生物细胞治疗中心 郑州 450052 2)郑州大学第一附属医院肿瘤中心 郑州 450052 3)河南省肿瘤免疫和生物治疗重点实验室 郑州 450052 4)郑州大学基础医学院免疫学教研室 郑州 450001 5)郑州大学生命科学学院 郑州 450001
Author(s):
LIU Yulin123) ZHANG Zhen13) CAO Ling14) SHEN Chunyi123) ZHANG Yi1235)
1)Biotherapy Center, the First Affiliated Hospital,Zhengzhou University, Zhengzhou 450052 2)Cancer Center, the First Affiliated Hospital,Zhengzhou University, Zhengzhou 450052 3)Henan Key Laboratory for Tumor Immunotherapy and Biotherapy,Zhengzhou 450052 4)Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001 5)School of Life Sciences, Zhengzhou University, Zhengzhou 450001
关键词:
吲哚加双氧酶1 犬尿酸 间皮素CAR-T细胞 食管癌 免疫治疗
Keywords:
IDO1 kynurenine mesothelin-CAR-T cell esophagus cancer immunotherapy
分类号:
R735.1
DOI:
10.13705/j.issn.1671-6825.2019.02.042
摘要:
目的:探讨食管癌组织中吲哚加双氧酶1(IDO1)的表达,及其代谢产物犬尿酸对间皮素嵌合抗原受体T细胞(CAR-T)功能的影响。方法:利用癌症基因组图谱(TCGA)数据库中数据分析食管癌组织中IDO1的表达对患者生存的影响; 采用密度梯度离心法获得健康供者外周血单个核细胞,并用细胞免疫磁珠分选出CD8+T细胞; 采用病毒感染的方法制备间皮素CAR-T细胞,用200 μmol/L犬尿酸处理48 h后,采用流式细胞术检测细胞表面标志物的表达和细胞内因子分泌的水平,检测其对KYSE510细胞的杀伤能力。以未用犬尿酸处理的间皮素CAR-T细胞作对照。结果:高表达IDO1的食管癌患者预后较差。与对照组相比,犬尿酸处理组间皮素CAR-T细胞表面抑制性分子PD-1表达上调(P<0.05),而激活性分子CD28表达下降(P<0.05),效应因子IFN-γ和IL-2分泌减少(P<0.05); 与KYSE510细胞共孵育后,间皮素CAR-T细胞CD107a表达降低,杀伤能力下降(P<0.05)。结论:犬尿酸可以抑制间皮素CAR-T细胞的功能。
Abstract:
Aim:To investigate the expression of IDO1 and the effects of IDO1 metabolite kynurenine on the function of mesothelin-CAR-T cells.Methods:The expression of IDO1 in esophagus cancer and its effects on patients'survival were analyzed using TCGA database. The peripheral blood mononuclear cells of healthy donors were isolated by density gradient centrifugation, and then the CD8+T cells were sorted using immunomagnetic beads.Mesothelin-CAR-T cells were prepared by virus infection.After being treated by 200 μmol/L kynurenine for 48 hours, the surface markers and cytokine production of mesothelin-CAR-T cells were determined by flow cytometry. Mesothelin-CAR-T cells were co-incubated with esophagus cancer KYSE510 cells, and flow cytometry was used to detect the effects of kynurenine on the killing function of mesothelin-CAR-T cells.The cells not treated were the control.Results:Esophagus cancer patients with overexpressed IDO1 had a poor prognosis. Compared with control group, kynurenine could induce the up-regulation of the immune checkpoint PD-1 on mesothelin-CAR-T cells(P<0.05), and down-regulation expression of activated marker CD28(P<0.05). Moreover, kynurenine could also inhibit the cytokines IFN-γ and IL-2 secretion of mesothelin-CAR-T cells(P<0.05). After co-incubation with tumor cells, kynurenine inhibited the killing function of mesothelin-CAR-T cells(P<0.05).Conclusion:Kynurenine can inhibit the function of mesothelin-CAR-T cells.

参考文献/References:

[1] 张毅,Michael Nishimura.肿瘤的细胞免疫治疗[J].郑州大学学报(医学版),2011,46(2):165
[2] LIU SV,GIACCONE G.First-line immunotherapy in lung cancer-taking the first step[J].Nat Rev Clin Oncol,2016,13(10):595
[3] VAN DER STEGEN SJ.HAMIEH M,SADELAIN M.The pharmacology of second-generation chimeric antigen receptors[J].Nat Rev Drug Discov,2015,14(7):499
[4] 曹玲,张毅.嵌合抗原受体修饰T细胞治疗恶性肿瘤的研究进展[J].兰州大学学报(医学版),2015,41(1):1
[5] NEWICK K, O'BRIEN S, MOON E, et al. CAR T cell therapy for solid tumors[J]. Annu Rev Med, 2017, 68:139
[6] 黄岚,张毅.肿瘤微环境中T细胞功能障碍及其逆转策略[J].中国肿瘤生物治疗杂志,2017,24(11):1247
[7] HORNYAK L,DOBOS N,KONCZ G,et al.The role of indoleamine-2,3-Dioxygenase in cancer development, diagnostics, and therapy[J].Front Immunol,2018,9:151
[8] TRIPLETT TA,GARRISON KC,MARSHALL NA,et al.Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme[J].Nat Biotechnol,2018,36(8):758
[9] CHEN W,ZHENG R,BAADE PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115
[10]乔亚敏,张毅.食管癌免疫治疗的现状及展望[J].世界华人消化杂志,2016,24(36):4739
[11]田永贵,张震,尹婕,等.不同亚群CD8+T细胞表型、功能分子及分化相关基因的表达[J].郑州大学学报(医学版),2019,54(3):318
[12]BEATTY GL,O'HARA MH,LACEY SF,et al.Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial[J].Gastroenterology,2018,155(1):29
[13]BEATTY GL,O'HARA M.Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps[J].Pharmacol Ther,2016,166:30
[14]MACKENZIE CR,HADDING U,DAUBENER W.Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci[J].J Infect Dis,1998,178(3):875
[15]BABCOCK TA,CARLIN JM.Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells[J].Cytokine,2000,12(6):588
[16]O'ROURKE DM,NASRALLAH MP,DESAI AA,et al.A single dose of peripherally infused EGFR Ⅷ-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma[J].Sci Transl Med,2017.doi:10.1126/scitranslmed.aaa0984
[17]LIU YY,LIANG XY,DONG WQ,et al.Tumor-repopulating cells induce PD-1 expression in CD8+T cells by transferring kynurenine and AhR activation[J].Cancer Cell,2018,33(3):480
[18]NGUYEN NT,KIMURA A,NAKAHAMA T,et al.Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism[J].Proc Natl Acad Sci USA,2010,107(46):19961
[19]MEZRICH JD,FECHNER JH,ZHANG X,et al.An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells[J].J Immunol,2010,185(6):3190

备注/Memo

备注/Memo:
【基金项目】国家自然科学基金资助项目(81771781,U1804281,81802857); 国家重点研发计划重点专项基金资助项目(2018YFC1313400); 河南省重大科技专项基金资助项目(161100311000)
【作者简介】张毅,通信作者,男,1964年4月生,博士,教授,主任医师,研究方向:肿瘤免疫治疗的机制和临床转化,E-mail:yizhang@zzu.edu.cn
更新日期/Last Update: 2019-05-20