内质网应激对T细胞抗肿瘤功能调控的研究进展
Research progress of T cell anti-tumor function regulated by endoplasmic reticulum stress
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摘要: 内质网应激参与肿瘤的发生与发展,近年来,内质网应激对T细胞发育和功能调控的研究也逐渐深入。肿瘤微环境中浸润的T细胞内质网应激的发生加剧T细胞的耗竭,损害T细胞抗肿瘤免疫功能。内质网应激抑制剂的使用可以减轻T细胞的耗竭程度,改善肿瘤微环境中T细胞的抗肿瘤功能。此外,一些时钟基因如Per1和Per2的下调也促进了T细胞耗竭的进展,而内质网应激通路的效应分子能够调控生物钟网络中Per基因家族的转录,增强T细胞的免疫功能。本文就内质网应激调控T细胞的抗肿瘤功能进行论述,为肿瘤免疫治疗提供新策略。Abstract: Endoplasmic reticulum (ER) stress is involved in the development and progression of tumors.In recent years, great attention has been paid to the study of the interplay of ER stress and T cell differentiation and functionality.Intense ER stress in the tumor-infiltrating T cells exacerbates T cell exhaustion and impairs T cell anti-tumor immunity.Therefore, a variety of ER stress inhibitors have been developed and utilized to alleviate T cell exhaustion, which improves T cell function in tumor microenvironment.Furthermore, the downregulation of several circadian clock genes like Per1 and Per2 also aggravates T cell exhaustion, and the key downstream effector molecules in ER stress regulate the transcription of Per family, thus enhancing the T cell function.In the present manuscript, we particularly summarize how ER stress impacts the anti-tumor immunity of T cells, and further discuss potential strategies for improving tumor immunotherapy via targeting ER stress.
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Keywords:
- endoplasmic reticulum stress /
- T cell /
- anti-tumor immunity /
- progress
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学报》是由教育部主管、中国药科大学主办的国家级药学学术刊物,被国内外重要检索数据库收录,为中国中文核心期刊、中国科学引文数据库(CSCD)核心期刊、中国精品科技期刊及中国高校百佳科技期刊。主要报道药学学科创新性科研成果,登载合成药物化学 、天然药物化学、中药学、药剂学、药物分析学、药物代谢动力学、生物技术、生物制药工程、药理学及其他相关学科的研究成果和学术动态。本刊为双月刊,128页,国内外公开发行。1. 稿件受理和注意事项
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基金项目 国家自然科学基金项目(No.59637050)
This study was supported by the National Natural Science Foundation of China(No.59637050)
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作者只列3人,后面加“et al”,姓名采用姓前名后著录法,西文刊名缩写按 Index Medicus,不要缩写点,中文刊名用英文缩写名称,括号内加注中文期刊的刊名。
[序号] 作者. 题名[J]. 刊名, 年, 卷(期): 起止页码.
[1] Zhang JY, Zhang JS, Zhang Y, et al. Studies on the intes-tinal absorption of crocin in rats and determination of the partition coefficient[J]. J China Pharm Univ(中国药科大学学报), 2004, 35(3): 283-284.
[2] Zhang HH, Kumar S, Barnett AH, et al. C eiling culture of mature human adipocytes:use in studies of adipocyte functions[J]. J Endocrinol, 2000, 164(1/2): 119-128.
专 著
[序号] 编者. 书名[M]. 版本(第 1 版不写). 出版地: 出版者, 出版年: 起止页码.
[3] Qi RM, Wang ZG, Wang SQ. Advances in Pharmacology (药理学进展)[M]. Beijing: People’s Medical Publish-ing House, 2003: 74.
[4] Peebles PZ, Jr. Probability, Random Rariable, and Ran-dom Signal Principles[M]. 4th ed. New York: McGraw Hill, 2001: 149.
标 准
[序号] 起草责任著. 标准代号 标准序号—发布年 标准名称[S]. 出版地: 出版者, 出版年: 引文页码.
[5] China Association for Standardization. GB/T 21853−2008 Chemicals−Partition Coeficient ( n-octanol/water)−Shake Flask Method [化学品分配系数(正丁醇-水)摇瓶法试验][S]. Beijing: Standards Press of China, 2008.
[6] Chinese Pharmacopoeia Commission. Chinese Pharmaco-poeia: part 2( 中华人民共和国药典:二部)[S]. Bei-jing: China Medical Science Press, 2010: 310-312 .
专利文献
[序号] 专利申请者或所有者.专利题名: 专利号[ P]. 公 告日期或公开日期[引用日期].
[7] Lafon L. New benzhydrysulphinyl derivatives: 4066686A[P]. 1978-01-03[2011-10-25].
电子文献
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[8] U. S. Food and Drug Administration. FDA approves shard system REMS for TIRF products[EB/OL].(2011-12-29)[2012-01-13]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm285345.htm.
学位论文
[序号] 作者.题名[D]. 保存地: 保存单位, 年份.
[9] Tian Z. Study of the clinical anti-aggregating effect of picotamide on platelet(吡考他胺抗血小板聚集性的临床研究)[D]. Changchun: Jilin University, 2004.
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-
[1] . Nat Rev Cancer,2021,21(2):71-88. [2] Hetz C,Zhang KZ,Kaufman RJ. Mechanisms,regulation and functions of the unfolded protein response[J]. Nat Rev Mol Cell Biol,2020,21(8):421-438. [3] Tavernier Q,Bennana E,Poindessous V,et al. Regulation of IRE1 RNase activity by the ribonuclease inhibitor 1 (RNH1)[J]. Cell Cycle,2018,17(15):1901-1916. [4] Chapman NM,Boothby MR,Chi HB. Metabolic coordination of T cell quiescence and activation[J]. Nat Rev Immunol,2020,20(1):55-70. [5] Ruterbusch M,Pruner K,Shehata L,et al. In vivo CD4+ T cell differentiation and function:revisiting the Th1/Th2 paradigm[J]. Annu Rev Immunol,2020,38(1):705-725. [6] Raskov H,Orhan A,Christensen JP,et al. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy[J]. Br J Cancer,2021,124(2):359-367. [7] Lin YN,Jiang M,Chen WJ,et al. Cancer and ER stress:mutual crosstalk between autophagy,oxidative stress and inflammatory response[J]. Biomed Pharmacother,2019,118:109249. [8] Walter P,Ron D. The unfolded protein response:from stress pathway to homeostatic regulation[J]. Science,2011,334(6059):1081-1086. [9] Di Conza G,Ho PC. ER stress responses:an emerging modulator for innate immunity[J]. Cells,2020,9(3):695. [10] Vattem KM,Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells[J]. Proc Natl Acad Sci U S A,2004,101(31):11269-11274. [11] Costa-Mattioli M,Walter P. The integrated stress response:from mechanism to disease[J]. Science,2020,368(6489): eaat5314 .[12] García-González P,Cabral-Miranda F,Hetz C,et al. Interplay between the unfolded protein response and immune function in the development of neurodegenerative diseases[J]. Front Immunol,2018,9(11):2541. [13] Kaspar S,Oertlin C,Szczepanowska K,et al. Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR[J]. Sci Adv,2021,7(22): eabf0971 .[14] Wortel IMN,van der Meer LT,Kilberg MS,et al. Surviving stress:modulation of ATF4-mediated stress responses in normal and malignant cells[J]. Trends Endocrinol Metab,2017,28(11):794-806. [15] Acosta-Alvear D,Karag?z GE,Fr?hlich F,et al. The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1[J]. eLife,2018,7: e43036 .[16] Belyy V,Tran NH,Walter P. Quantitative microscopy reveals dynamics and fate of clustered IRE1α[J]. Proc Natl Acad Sci U S A,2020,117(3):1533-1542. [17] Chen SS,Chen J,Hua X,et al. The emerging role of XBP1 in cancer[J]. Biomed Pharmacother,2020,127:110069. [18] Yoshida H,Matsui T,Hosokawa N,et al. A time-dependent phase shift in the mammalian unfolded protein response[J]. Dev Cell,2003,4(2):265-271. [19] Lee AH,Iwakoshi NN,Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response[J]. Mol Cell Biol,2003,23(21):7448-7459. [20] Wang JM,Qiu YN,Yang ZQ,et al. Inositol-requiring enzyme 1 facilitates diabetic wound healing through modulating microRNAs[J]. Diabetes,2017,66(1):177-192. [21] Haze K,Yoshida H,Yanagi H,et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress[J]. Mol Biol Cell,1999,10(11):3787-3799. [22] Hetz C,Papa FR. The unfolded protein response and cell fate control[J]. Mol Cell,2018,69(2):169-181. [23] Bettigole SE,Glimcher LH. Endoplasmic reticulum stress in immunity[J]. Annu Rev Immunol,2015,33:107-138. [24] Wu J,Rutkowski DT,Dubois M,et al. ATF6α optimizes long-term endoplasmic Reticulum function to protect cells from chronic stress[J]. Dev Cell,2007,13(3):351-364. [25] Glembotski CC,Arrieta A,Blackwood EA,et al. ATF6 as a nodal regulator of proteostasis in the heart[J]. Front Physiol,2020,11:267. [26] Cao Y,Trillo-Tinoco J,Sierra RA,et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression[J]. Nat Commun,2019,10(1):1280. [27] Hurst KE,Lawrence KA,Essman MT,et al. Endoplasmic Reticulum stress contributes to mitochondrial exhaustion of CD8 + T cells[J]. Cancer Immunol Res,2019,7(3):476-486. [28] Eggenhuizen PJ,Ng BH,Ooi JD. Treg enhancing therapies to treat autoimmune diseases[J]. Int J Mol Sci,2020,21(19):7015. [29] Feng ZZ,Luo N,Liu Y,et al. ER stress and its PERK branch enhance TCR-induced activation in regulatory T cells[J]. Biochem Biophys Res Commun,2021,563:8-14. [30] Song M,Sandoval TA,Chae CS,et al. IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity[J]. Nature,2018,562(7727):423-428. [31] Ma XZ,Bi EG,Lu Y,et al. Cholesterol induces CD8 + T cell exhaustion in the tumor microenvironment[J]. Cell Metab,2019,30(1):143-156.e5. [32] Urano F,Wang X,Bertolotti A,et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1[J]. Science,2000,287(5453):664-666. [33] Coleman OI,Lobner EM,Bierwirth S,et al. Activated ATF6 induces intestinal dysbiosis and innate immune response to promote colorectal tumorigenesis[J]. Gastroenterology,2018,155(5):1539-1552.e12. [34] Wang Q,Zhu XY,Li ZJ,et al. ATF6 promotes liver fibrogenesis by regulating macrophage-derived interleukin-1α expression[J]. Cell Immunol,2021,367:104401. [35] Tcyganov EN,Hanabuchi S,Hashimoto A,et al. Distinct mechanisms govern populations of myeloid-derived suppressor cells in chronic viral infection and cancer[J]. J Clin Invest,2021,131(16): e145971 .[36] Marciniak SJ,Chambers JE,Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease[J]. Nat Rev Drug Discov,2022,21(2):115-140. [37] Lebeaupin C,Vallée D,Rousseau D,et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice[J]. Hepatology,2018,68(2):515-532. [38] di Conza G,Tsai CH,Gallart-Ayala H,et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity[J]. Nat Immunol,2021,22(11):1403-1415. [39] Bross PF,Kane R,Farrell AT,et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma[J]. Clin Cancer Res,2004,10(12 Pt 1 ):3954-3964.[40] Atkins C,Liu Q,Minthorn E,et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity[J]. Cancer Res,2013,73(6):1993-2002. [41] Yu QJ,Zhao B,Gui J,et al. Type I interferons mediate pancreatic toxicities of PERK inhibition[J]. Proc Natl Acad Sci U S A,2015,112(50):15420-15425. [42] Takahashi JS. Transcriptional architecture of the mammalian circadian clock[J]. Nat Rev Genet,2017,18(3):164-179. [43] Nobis CC,Dubeau Laramée G,Kervezee L,et al. The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways[J]. Proc Natl Acad Sci U S A,2019,116(40):20077-20086. [44] Yang X,Xia R,Yue CH,et al. ATF4 regulates CD4+ T cell immune responses through metabolic reprogramming[J]. Cell Rep,2018,23(6):1754-1766. [45] Yu XF,Rollins D,Ruhn KA,et al. TH17 cell differentiation is regulated by the circadian clock[J]. Science,2013,342(6159):727-730. [46] Yuan GS,Hua BX,Cai TT,et al. Clock mediates liver senescence by controlling ER stress[J]. Aging,2017,9(12):2647-2665. [47] Gao L,Chen HT,Li CM,et al. ER stress activation impairs the expression of circadian clock and clock-controlled genes in NIH3T3 cells via an ATF4-dependent mechanism[J]. Cell Signal,2019,57:89-101. [48] Zhang Z,Zeng PH,Gao WH,et al. Circadian clock:a regulator of the immunity in cancer[J]. Cell Commun Signal,2021,19(1):37. [49] Pluquet O,Dejeans N,Bouchecareilh M,et al. Posttranscriptional regulation of PER1 underlies the oncogenic function of IREα[J]. Cancer Res,2013,73(15):4732-4743. [50] Pluquet O,Dejeans N,Chevet E. Watching the clock:endoplasmic reticulum-mediated control of circadian rhythms in cancer[J]. Ann Med,2014,46(4):233-243. [51] Wu YC,Tao BR,Zhang TY,et al. Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion[J]. Front Immunol,2019,10:2451. [52] Pathak SS,Liu D,Li TB,et al. The eIF2α kinase GCN2 modulates period and rhythmicity of the circadian clock by translational control of Atf4[J]. Neuron,2019,104(4):724-735.e6. [53] Wang GH,Yang ZQ,Zhang KZ. Endoplasmic reticulum stress response in cancer:molecular mechanism and therapeutic potential[J]. Am J Transl Res,2010,2(1):65-74. [54] Kamimura D,Bevan MJ. Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection[J]. J Immunol,2008,181(8):5433-5441. -
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