检验医学 ›› 2024, Vol. 39 ›› Issue (4): 317-323.DOI: 10.3969/j.issn.1673-8640.2024.04.002
收稿日期:
2023-10-25
修回日期:
2024-01-18
出版日期:
2024-04-30
发布日期:
2024-05-07
通讯作者:
卢仁泉,E-mail:lurenquan@126.com。
作者简介:
张 珩,女,1994年生,博士,主管技师,主要从事临床检验工作。
基金资助:
ZHANG Heng, ZHENG Hui, LU Renquan()
Received:
2023-10-25
Revised:
2024-01-18
Online:
2024-04-30
Published:
2024-05-07
摘要:
卵巢癌是导致女性癌症死亡的主要原因之一。虽然免疫治疗方法已用于卵巢癌的临床治疗,但有效率较低。肿瘤微环境中存在免疫抑制因素,提示免疫系统失衡与卵巢癌进展密切相关。调节性T细胞(Treg)是一群发挥抑制效应的T细胞亚群,作为维持自身免疫耐受的重要组成部分,是肿瘤免疫、自身免疫和维持机体免疫稳态的关键。Treg在卵巢癌微环境中发挥重要作用,参与介导免疫耐受,影响卵巢癌的进展和预后。文章对卵巢癌微环境调控Treg的研究进展进行总结。
中图分类号:
张珩, 郑慧, 卢仁泉. 卵巢癌微环境调控调节性T细胞的研究进展[J]. 检验医学, 2024, 39(4): 317-323.
ZHANG Heng, ZHENG Hui, LU Renquan. Research progress on the regulation of regulatory T cells in ovarian cancer tumor microenvironment[J]. Laboratory Medicine, 2024, 39(4): 317-323.
[1] |
SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer ctatistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
DOI URL |
[2] |
LAMPERT E J, CIMINO-MATHEWS A, LEE J S, et al. Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses[J]. J Immunother Cancer, 2020, 8(2):e000516.
DOI URL |
[3] |
KANDALAFT L E, DANGAJ LANITI D, COUKOS G. Immunobiology of high-grade serous ovarian cancer:lessons for clinical translation[J]. Nat Rev Cancer, 2022, 22(11):640-656.
DOI |
[4] |
MIKAMI N, SAKAGUCHI S. Regulatory T cells in autoimmune kidney diseases and transplantation[J]. Nat Rev Nephrol, 2023, 19(9):544-557.
DOI PMID |
[5] |
ERNST P B, GARRISON J C, THOMPSON L F. Much ado about adenosine:adenosine synthesis and function in regulatory T cell biology[J]. J Immunol, 2010, 185(4):1993-1998.
DOI URL |
[6] |
JOLLER N, LOZANO E, BURKETT P R, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses[J]. Immunity, 2014, 40(4):569-581.
DOI PMID |
[7] |
DIKIY S, RUDENSKY A Y. Principles of regulatory T cell function[J]. Immunity, 2023, 56(2):240-255.
DOI URL |
[8] |
GROSSMAN W J, VERBSKY J W, BARCHET W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death[J]. Immunity, 2004, 21(4):589-601.
DOI PMID |
[9] |
TOGASHI Y, SHITARA K, NISHIKAWA H. Regulatory T cells in cancer immunosuppression-implications for anticancer therapy[J]. Nat Rev Clin Oncol, 2019, 16(6):356-371.
DOI |
[10] |
PANKOWSKA K A, BDKOWSKA G E, CHOCIEJ-STYPUŁKOWSKA J, et al. Crosstalk of immune cells and platelets in an ovarian cancer microenvironment and their prognostic significance[J]. Int J Mol Sci, 2023, 24(11):9279.
DOI URL |
[11] |
LAUMONT C M, WOUTERS M C A, SMAZYNSKI J, et al. Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39,CD103,and PD-1 in ovarian cancer[J]. Clin Cancer Res, 2021, 27(14):4089-4100.
DOI URL |
[12] |
JEON S H, KANG M, JEON M, et al. CEACAM1 marks highly suppressive intratumoral regulatory T cells for targeted depletion therapy[J]. Clin Cancer Res, 2023, 29(9):1794-1806.
DOI URL |
[13] | AHMADZADEH M, PASETTO A, JIA L, et al. Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity[J]. Sci Immunol, 2019, 4(31):eaao4310. |
[14] | 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. |
[15] |
TOKER A, NGUYEN L T, STONE S C, et al. Regulatory T cells in ovarian cancer are characterized by a highly activated phenotype distinct from that in melanoma[J]. Clin Cancer Res, 2018, 24(22):5685-5696.
DOI PMID |
[16] |
LEVEQUE L, DEKNUYDT F, BIOLEY G, et al. Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells[J]. J Immunother, 2009, 32(2):101-108.
DOI PMID |
[17] |
DRERUP J M, DENG Y, PANDESWARA S L, et al. CD122-selective IL2 complexes reduce immunosuppression,promote Treg fragility,and sensitize tumor response to PD-L1 blockade[J]. Cancer Res, 2020, 80(22):5063-5075.
DOI URL |
[18] | OH S A, LIU M, NIXON B G, et al. Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance[J]. Proc Natl Acad Sci U S A, 2017, 114(36):E7536-E7544. |
[19] |
ROANE B M, MEZA-PEREZ S, KATRE A A, et al. Neutralization of TGFβ improves tumor immunity and reduces tumor progression in ovarian carcinoma[J]. Mol Cancer Ther, 2021, 20(3):602-611.
DOI PMID |
[20] |
HAMPRAS S S, SUCHESTON-CAMPBELL L E, CANNIOTO R, et al. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer[J]. Oncotarget, 2016, 7(43):69097-69110.
DOI PMID |
[21] |
CURIEL T J, COUKOS G, ZOU L, 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.
DOI PMID |
[22] |
NOY R, POLLARD J W. Tumor-associated macrophages:from mechanisms to therapy[J]. Immunity, 2014, 41(1):49-61.
DOI URL |
[23] |
THIBODEAUX S R, BARNETT B B, PANDESWARA S, et al. IFNα augments clinical efficacy of regulatory T-cell depletion with denileukin diftitox in ovarian cancer[J]. Clin Cancer Res, 2021, 27(13):3661-3673.
DOI URL |
[24] |
FACCIABENE A, PENG X, HAGEMANN I S, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells[J]. Nature, 2011, 475(7355):226-230.
DOI |
[25] |
GOBERT M, TREILLEUX I, BENDRISS-VERMARE N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome[J]. Cancer Res, 2009, 69(5):2000-2009.
DOI PMID |
[26] |
HIROTA K, YOSHITOMI H, HASHIMOTO M, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model[J]. J Exp Med, 2007, 204(12):2803-2812.
DOI URL |
[27] | GLATIGNY S, DUHEN R, ARBELAEZ C, et al. Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4[J]. Sci Rep, 2015,5:7834. |
[28] |
FRICK V O, RUBIE C, KEILHOLZ U, et al. Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy:an overview[J]. World J Gastroenterol, 2016, 22(2):833-841.
DOI URL |
[29] |
ZENG Y, LI B, LIANG Y, et al. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment[J]. FASEB J, 2019, 33(5):6596-6608.
DOI PMID |
[30] |
IDORN M, OLSEN M, HALLDÓRSDÓTTIR H R, et al. Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction[J]. Oncoimmunology, 2018, 7(4):e1412029.
DOI URL |
[31] | TAN C L, KUCHROO J R, SAGE P T, et al. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance[J]. J Exp Med, 2021, 218(1):e20182232. |
[32] |
SATO S, MATSUSHITA H, SHINTANI D, et al. Association between effector-type regulatory T cells and immune checkpoint expression on CD8+ T cells in malignant ascites from epithelial ovarian cancer[J]. BMC Cancer, 2022, 22(1):437.
DOI |
[33] |
PARVATHAREDDY S K, SIRAJ A K, AL-BADAWI I A, et al. Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation[J]. Sci Rep, 2021, 11(1):3750.
DOI PMID |
[34] | KAMPAN N C, MADONDO M T, MCNALLY O M, et al. Interleukin 6 present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells[J]. Front Immunol, 2017,8:1482. |
[35] |
GOVINDARAJ C, SCALZO-INGUANTI K, MADONDO M, et al. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment[J]. Clin Immunol, 2013, 149(1):97-110.
DOI PMID |
[36] | TORREY H, BUTTERWORTH J, MERA T, et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs[J]. Sci Signal, 2017, 10(462):eaaf8608. |
[37] |
CHEN X, WU X, ZHOU Q, et al. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment[J]. J Immunol, 2013, 190(3):1076-1084.
DOI PMID |
[38] | DE LEVE S, WIRSD RFER F, JENDROSSEK V. Targeting the immunomodulatory CD73/adenosine system to improve the therapeutic gain of radiotherapy[J]. Front Immunol, 2019,10:698. |
[39] |
CHEN F, XU Y, CHEN Y, et al. TIGIT enhances CD4+ regulatory T-cell response and mediates immune suppression in a murine ovarian cancer model[J]. Cancer Med, 2020, 9(10):3584-3591.
DOI URL |
[40] |
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.
DOI PMID |
[41] |
FIALOVÁ A, PARTLOVÁ S, SOJKA L, et al. Dynamics of T-cell infiltration during the course of ovarian cancer:the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells[J]. Int J Cancer, 2013, 132(5):1070-1079.
DOI URL |
[42] |
SOLVAY M, HOLFELDER P, KLAESSENS S, et al. Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake,and potentiates induction of regulatory T lymphocytes[J]. J Immunother Cancer, 2023, 11(6):e006728.
DOI URL |
[43] |
XU R, WU M, LIU S, et al. Glucose metabolism characteristics and TLR8-mediated metabolic control of CD4+ Treg cells in ovarian cancer cells microenvironment[J]. Cell Death Dis, 2021, 12(1):22.
DOI |
[44] | ZHANG Y, XU L, ZHOU B, et al. Transcription factor FOXP3 gene variants affect epithelial ovarian carcinoma in the Han Chinese population[J]. Int J Clin Exp Pathol, 2018, 11(3):1684-1693. |
[45] |
MCCAW T R, GOEL N, BROOKE D J, et al. Class Ⅰ histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer[J]. Cancer Med, 2021, 10(2):709-717.
DOI URL |
[46] |
ZHANG L, DOU X, ZHENG Z, et al. YTHDF2/m6A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs[J]. EMBO J, 2023, 42(15):e113126.
DOI URL |
[47] | QIN S, LIU G, JIN H, et al. The comprehensive expression and functional analysis of m6A modification "readers" in hepatocellular carcinoma[J]. Aging(Albany NY), 2022, 14(15):6269-6298. |
[48] |
JONULEIT H, SCHMITT E, SCHULER G, et al. Induction of interleukin 10-producing,nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells[J]. J Exp Med, 2000, 192(9):1213-1222.
DOI URL |
[49] |
CONRAD C, GREGORIO J, WANG Y H, et al. Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells[J]. Cancer Res, 2012, 72(20):5240-5249.
DOI PMID |
[50] |
TANIZAKI Y, KOBAYASHI A, TOUJIMA S, et al. Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment[J]. Cancer Sci, 2014, 105(8):966-973.
DOI URL |
[51] |
HOECHST B, GAMREKELASHVILI J, MANNS M P, et al. Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells[J]. Blood, 2011, 117(24):6532-6541.
DOI PMID |
[52] | PAN P Y, MA G, WEBER K J, et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer[J]. Cancer Res, 2010, 70(1):99-108. |
[53] | YANG Y, YANG Y, YANG J, et al. Tumor microenvironment in ovarian cancer:function and therapeutic strategy[J]. Front Cell Dev Biol, 2020,8:758. |
[54] |
GIVEL A M, KIEFFER Y, SCHOLER-DAHIREL A, et al. MiR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers[J]. Nat Commun, 2018, 9(1):1056.
DOI |
[55] | THEODORAKI M N, YERNENI S, SARKAR S N, et al. Helicase-driven activation of NFκB-COX2 pathway mediates the immunosuppressive component of dsRNA-driven inflammation in the human tumor microenvironment[J]. Cancer Res, 2018, 78(15):4292-4302. |
[56] |
ZHOU J, LI X, WU X, et al. Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer[J]. Cancer Immunol Res, 2018, 6(12):1578-1592.
DOI PMID |
[57] |
JIMÉNEZ-SÁNCHEZ A, CYBULSKA P, MAGER K L, et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy[J]. Nat Genet, 2020, 52(6):582-593.
DOI |
[58] |
WANDERLEY C W, COLÓN D F, LUIZ J P M, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner[J]. Cancer Res, 2018, 78(20):5891-5900.
DOI PMID |
[59] | KOUIDHI S, BEN AYED F, BENAMMAR ELGAAIED A. Targeting tumor metabolism:a new challenge to improve immunotherapy[J]. Front Immunol, 2018,9:353. |
[60] | AHMED N, ESCALONA R, LEUNG D, et al. Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells:perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells[J]. Semin Cancer Biol, 2018,53:265-281. |
[61] |
GHIRINGHELLI F, MENARD C, PUIG P E, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients[J]. Cancer Immunol Immunother, 2007, 56(5):641-648.
DOI URL |
[62] |
AUDIA S, NICOLAS A, CATHELIN D, et al. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma:a Phase Ⅰ clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes[J]. Clin Exp Immunol, 2007, 150(3):523-530.
DOI URL |
[63] |
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(1):4011.
DOI PMID |
[64] |
DWARAKANATH B, JAIN V. Targeting glucose metabolism with 2-deoxy-D-glucose for improving cancer therapy[J]. Future Oncol, 2009, 5(5):581-585.
DOI PMID |
[65] |
CORREALE P, CUSI M G, TSANG K Y, et al. Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients[J]. J Clin Oncol, 2005, 23(35):8950-8958.
DOI PMID |
[66] |
KANG Y, FLORES L, NGAI H W, et al. Large,anionic liposomes enable targeted intraperitoneal delivery of a TLR 7/8 agonist to repolarize ovarian tumors' microenvironment[J]. Bioconjug Chem, 2021, 32(8):1581-1592.
DOI URL |
[1] | 程燕, 张宁, 董黎, 凌箫鸣, 王悦, 陈贵芹, 靖爽, 陈雁南. MFG-E8和GNA14在子宫内膜异位症相关性卵巢癌中的表达及其临床意义[J]. 检验医学, 2024, 39(6): 530-535. |
[2] | 郑慧, 陈颖秀, 叶绿茵, 卢仁泉, 郭林. 结直肠癌患者外周血T淋巴细胞亚群与肿瘤进展的关系[J]. 检验医学, 2024, 39(4): 330-335. |
[3] | 周玉飞, 李云辉, 李冰熠, 侯青霞. C反应蛋白/白蛋白比值和系统免疫炎症指数与浆液性卵巢癌患者临床病理特征和预后的关系[J]. 检验医学, 2024, 39(4): 363-368. |
[4] | 梁臻龙, 郭宇妮, 王楠, 王佳楠, 刘佳玉, 刘培培, 向代军, 王成彬, 李绵洋. 造血干细胞移植患者术后淋巴细胞亚群水平在移植物抗宿主病中的临床意义[J]. 检验医学, 2024, 39(4): 387-392. |
[5] | 刘蓉, 王德刚. 卵巢癌组织中SIRT-1、CD44的表达及临床意义[J]. 检验医学, 2022, 37(7): 632-6358. |
[6] | 徐志刚, 卢霞, 龚晓霖. CA125、Fib、DD在卵巢癌化疗疗效评估中的价值[J]. 检验医学, 2022, 37(11): 1104-1105. |
[7] | 薛艳, 王佳佳, 王馥香, 任秋伟. CLIC4、SNHG3表达与Ⅰ~Ⅱ期卵巢癌患者预后的关系[J]. 检验医学, 2021, 36(10): 1026-1032. |
[8] | 杨焕, 周臣, 陆晓媛. 平均血小板体积与卵巢癌预后的相关性分析[J]. 检验医学, 2020, 35(12): 1255-1258. |
[9] | 邹广慧, 孙奋勇, 戴佳奇, 严杰, 张云, 殷志强. 滤泡调节性T细胞在桥本甲状腺炎中的作用[J]. 检验医学, 2019, 34(8): 682-686. |
[10] | 柯星, 张良, 沈立松. CD4+CD25highCD127low调节性T细胞促进上皮性卵巢癌转移机制的初步探讨[J]. 检验医学, 2019, 34(2): 110-115. |
[11] | 黄群欢, 洪岭, 陶春林, 黄旭红. 不同分期宫颈癌患者外周血Treg和相关细胞因子差异分析[J]. 检验医学, 2017, 32(9): 769-772. |
[12] | 徐鑫鑫, 王运刚, 蔡花, 沈培, 褚福营. 三维适形放射治疗联合化疗对食管癌患者外周血Treg的影响[J]. 检验医学, 2017, 32(5): 390-393. |
[13] | 何华, 胡蓉, 李峰, 朱亚飞, 任苓, 江丽霞. 电化学发光法检测血清HE4、ROMA指数参考区间分析[J]. 检验医学, 2017, 32(5): 399-402. |
[14] | 宋斌斌, 潘柏申. 卵巢癌血清标志物的临床应用[J]. 检验医学, 2015, 30(8): 866-870. |
[15] | 杨婷婷, 王青, 李志, 朴君, 朴敬爱. 银屑病患者Th17和Treg细胞及其相关细胞因子的表达[J]. 检验医学, 2015, 30(7): 715-719. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||