内质网应激对T细胞抗肿瘤功能调控的研究进展

王铮豪; 高亚凤; 张连军; 刘畅

doi:10.11665/j.issn.1000-5048.20220502

内质网应激对T细胞抗肿瘤功能调控的研究进展

1.
中国药科大学生命科学与技术学院，南京 211198
2.
中国医学科学院北京协和医学院苏州系统医学研究所，苏州 215123

基金项目: 国家自然科学基金资助项目（No.81971466）；江苏省杰出青年基金资助项目（No.BK20220049）

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出版历程
- 收稿日期: 2022-08-07
- 修回日期: 2022-09-19
- 刊出日期: 2022-10-24

Research progress of T cell anti-tumor function regulated by endoplasmic reticulum stress

1.
School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198
2.
Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou 215123, China

Funds: This study was supported by the National Natural Science Foundation of China (No.81971466) and the Applied Basic Research Programs of Science and Technology Commission Foundation of Jiangsu Province (No.BK20220049)

摘要

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。
- 内质网应激 /
- T细胞 /
- 抗肿瘤功能 /
- 进展
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.
- endoplasmic reticulum stress /
- T cell /
- anti-tumor immunity /
- progress

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参考文献(54)

[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.