调节性T细胞在抗肿瘤免疫及治疗中的研究进展

doi:10.3969/j.issn.1004-616x.2022.06.015

摘要/Abstract

摘要： 调节性T细胞(Tregs)是以Foxp3为标志物的CD4⁺T细胞的一个亚群，它的存在是把双刃剑，一方面起着维持机体自身免疫耐受，避免免疫应答过度而损伤机体的重要作用，另一方面该细胞可促进肿瘤细胞逃避机体免疫监视和慢性感染。Tregs引起的肿瘤细胞免疫逃逸是肿瘤免疫治疗的主要障碍之一。Tregs存在有助于肿瘤的早期建立和进展，而Tregs缺失则会导致肿瘤进展延迟。因此，针对Tregs的免疫疗法在肿瘤临床治疗方面具有广泛的应用前景，本文将对Tregs在抗肿瘤免疫和治疗中的研究进展进行综述，旨在为肿瘤治疗提供新的靶点参考。

关键词: 调节性T细胞, 免疫逃逸, 肿瘤免疫, 肿瘤治疗

中图分类号:

R730.51

梁敏, 肖艳红, 刘艳灵, 王伟岩, 刘芹芹, 滕清良. 调节性T细胞在抗肿瘤免疫及治疗中的研究进展[J]. 癌变·畸变·突变, 2022, 34(6): 481-484.

参考文献

[1] XIA C F, DONG X S, LI H, et al. Cancer statistics in China and United States, 2022:profiles, trends, and determinants[J]. Chin Med J (Engl), 2022, 135(5):584-590.
[2] SAKAGUCHI S, SAKAGUCHI N, ASANO M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases[J]. J Immunol, 1995, 155(3):1151-1164.
[3] KUMAR P, SAINI S, PRABHAKAR B S. Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis[J]. Semin Cancer Biol, 2020, 64:29-35.
[4] GERSHON R K. A disquisition on suppressor T cells[J]. Immunol Rev, 1975, 26(1):170-185.
[5] HORI S, NOMURA T, SAKAGUCHI S. Control of regulatory T cell development by the transcription factor Foxp3[J]. Science, 2003, 299(5609):1057-1061.
[6] JANG S W, HWANG S S, KIM H S, et al. Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function[J]. Proc Natl Acad Sci USA, 2019, 116(51):25790-25799.
[7] ZHANG Z M, ZHOU X Y. Foxp3 instability helps tTregs distinguish self and non-self[J]. Front Immunol, 2019, 10:2226.
[8] CAMPBELL D J. Control of regulatory T cell migration, function, and homeostasis[J]. J Immunol, 2015, 195(6):2507-2513.
[9] SEO N, TOKURA Y, TAKIGAWA M, et al. Depletion of IL-10- and TGF-beta-producing regulatory gamma delta T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells[J]. J Immunol Baltim Md 1950, 1999, 163(1):242-9.
[10] TIMPERI E, BARNABA V. CD39 regulation and functions in T cells[J]. Int J Mol Sci, 2021, 22(15):8068.
[11] BAGHBANI E, NOOROLYAI S, SHANEHBANDI D, et al. Regulation of immune responses through CD39 and CD73 in cancer:novel checkpoints[J]. Life Sci, 2021, 282:119826.
[12] CHEN Q D, PU N, YIN H L, et al. CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer[J]. J Cell Mol Med, 2020, 24(15):8674-8686.
[13] GONZALEZ-JUNCA A, DRISCOLL K E, PELLICCIOTTA I, et al. Autocrine TGFβ is a survival factor for monocytes and drives immunosuppressive lineage commitment[J]. Cancer Immunol Res, 2019, 7(2):306-320.
[14] ZAIATZ-BITTENCOURT V, FINLAY D K, GARDINER C M. Canonical TGF-β signaling pathway represses human NK cell metabolism[J]. J Immunol, 2018, 200(12):3934-3941.
[15] LARSON C, ORONSKY B, CARTER C A, et al. TGF-beta:a master immune regulator[J]. Expert Opin Ther Targets, 2020, 24(5):427-438.
[16] QURESHI O S, ZHENG Y, NAKAMURA K, et al. Trans-endocytosis of CD80 and CD86:a molecular basis for the cell-extrinsic function of CTLA-4[J]. Science, 2011, 332(6029):600-603.
[17] DEES S, GANESAN R, SINGH S, et al. Regulatory T cell targeting in cancer:emerging strategies in immunotherapy[J]. Eur J Immunol, 2021, 51(2):280-291.
[18] RUPP T, GENEST L, BABIN D, et al. Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response[J]. Transl Oncol, 2022, 20:101405.
[19] BOTTICELLI A, CERBELLI B, LIONETTO L, et al. Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC-[J]. J Transl Med, 2018, 16(1):219.
[20] PENG Y, TAO Y, ZHANG Y, et al. CD25:a potential tumor therapeutic target[J]. Int J Cancer, 2022:2022.
[21] OLSEN E, DUVIC M, FRANKEL A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma[J]. J Clin Oncol, 2001, 19(2):376-388.
[22] CHEUNG L S, FU J, KUMAR P, et al. Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti-PD-1 in melanoma[J]. Proc Natl Acad Sci USA, 2019, 116(8):3100-3105.
[23] LI L, MA Y, XU Y. Follicular regulatory T cells infiltrated the ovarian carcinoma and resulted in CD8 T cell dysfunction dependent on IL-10 pathway[J]. Int Immunopharmacol, 2019, 68:81-87.
[24] ZHU J L, WANG Y, LI D, et al. Interleukin-35 promotes progression of prostate cancer and inhibits anti-tumor immunity[J]. Cancer Cell Int, 2020, 20:487.
[25] LIU Y Y, LIANG X Y, YIN X N, et al. Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells[J]. Nat Commun, 2017, 8:15207.
[26] ZHANG X, LIU X T, ZHOU W, et al. Blockade of IDO-kynurenine-AhR axis ameliorated colitis-associated colon cancer via inhibiting immune tolerance[J]. Cell Mol Gastroenterol Hepatol, 2021, 12(4):1179-1199.
[27] LIU Y, LIANG X, DONG W, 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):480-494.
[28] CAMPESATO L F, BUDHU S, TCHAICHA J, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine[J]. Nat Commun, 2020, 11:4011.
[29] CHANG D K, PETERSON E, SUN J, et al. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model[J]. Oncoimmunology, 2016, 5(3):e1090075.
[30] COUSSENS L M, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420(6917):860-867.
[31] CURIEL T J, COUKOS G, ZOU L H, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival[J]. Nat Med, 2004, 10(9):942-949.
[32] NEOPTOLEMOS J P, STOCKEN D D, BASSI C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection:a randomized controlled trial[J]. JAMA, 2010, 304(10):1073-1081.
[33] CONROY T, HAMMEL P, HEBBAR M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer[J]. N Engl J Med, 2018, 379(25):2395-2406.
[34] ROY I, BOYLE K A, VONDERHAAR E P, et al. Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma[J]. Lab Investig, 2017, 97(3):302-317.
[35] YAN J J, YUAN P K, GUI L M, et al. CCL28 downregulation attenuates pancreatic cancer progression through tumor cell-intrinsic and-extrinsic mechanisms[J]. Technol Cancer Res Treat, 2021, 20:15330338211068958.
[36] SARKAR T, DHAR S, CHAKRABORTY D, et al. FOXP3/HAT1 axis controls treg infiltration in the tumor microenvironment by inducing CCR4 expression in breast cancer[J]. Front Immunol, 2022, 13:740588.
[37] ISHITSUKA K. Diagnosis and management of adult T-cell leukemia/lymphoma[J]. Semin Hematol, 2021, 58(2):114-122.
[38] YOSHIE O. CCR4 as a therapeutic target for cancer immunotherapy[J]. Cancers, 2021, 13(21):5542.
[39] BARSHESHET Y, WILDBAUM G, LEVY E, et al. CCR8+ FOXp3+ Treg cells as master drivers of immune regulation[J]. PNAS, 2017, 114(23):6086-6091.
[40] WANG L, SIMONS D L, LU X Y, et al. Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer[J]. Nat Immunol, 2019, 20(9):1220-1230.
[41] CAMPBELL J R, MCDONALD B R, MESKO P B, et al. Fc-optimized anti-CCR8 antibody depletes regulatory T cells in human tumor models[J]. Cancer Res, 2021, 81(11):2983-2994.
[42] MAJ T, WANG W, CRESPO J, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor[J]. Nat Immunol, 2017, 18(12):1332-1341.
[43] KARPISHEH V, MOUSAVI S M, NAGHAVI SHEYKHOLESLAMI P, et al. The role of regulatory T cells in the pathogenesis and treatment of prostate cancer[J]. Life Sci, 2021, 284:119132.
[44] ZHOU G, DRAKE C G, LEVITSKY H I. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines[J]. Blood, 2006, 107(2):628-636.
[45] CHEVALIER M F, SCHNEIDER A K, CESSON V, et al. Conventional and PD-L1-expressing regulatory T cells are enriched during BCG therapy and may limit its efficacy[J]. Eur Urol, 2018, 74(5):540-544.