The changes and significance of TIGIT and PD-1 co-expression on Tfh cells in peripheral blood of patients with chronic lymphocytic leukemia
-
摘要: 目的 初步探讨慢性淋巴细胞白血病(chronic lymphocytic leukemia，CLL)患者外周血共抑制分子T细胞免疫球蛋白和ITIM结构域(T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain，TIGIT)和程序性细胞死亡受体1(programmed cell death protein 1，PD-1)在Tfh细胞上的表达变化特点及临床意义。方法 采用流式细胞术检测50例CLL患者、36例非CLL的慢性B淋巴细胞增殖疾病患者和30例健康者外周血Tfh细胞百分比和Tfh细胞上PD-1和TIGIT的水平，比较3组受试者的差异。分析CLL患者TIGIT+PD-1+Tfh细胞百分比与IPI评分分层的关系，以及与免疫球蛋白的相关性。结果 ① 与对照组比较，初诊CLL患者Tfh、PD-1+Tfh、TIGIT+Tfh、TIGIT+PD-1+Tfh、TIGIT+PD-1-Tfh和TIGIT-PD-1+Tfh细胞百分比明显增高，差异有统计学意义(P < 0.05)。②TIGIT+PD-1+Tfh细胞在CLL-IPI预后分层低危组、中危组、高危组、极高危组比较分析结果，组间和组内两两比较差异均有统计学意义(P < 0.05)，随着预后分层增加TIGIT+PD-1+Tfh细胞水平逐渐增加。③受试者工作特征曲线结果显示，TIGIT+PD-1+Tfh细胞在CLL患者和非CLL患者的鉴别诊断中具有一定的诊断价值(P < 0.05)。④Logistic回归分析显示，TIGIT+PD-1+Tfh细胞百分比是CLL发病的独立危险因素(P < 0.05)。⑤CLL患者外周血中TIGIT+PD-1+Tfh与IgA、IgM、IgG均呈负相关(P < 0.05)。结论 初诊CLL患者外周血TIGIT+PD-1+Tfh细胞百分比明显增加，Tfh细胞高表达共抑制分子TIGIT和PD-1参与CLL疾病的发生，并且与疾病的免疫球蛋白水平降低有关。
-
关键词:
- 慢性淋巴细胞白血病 /
- 滤泡辅助性T细胞 /
- 程序性细胞死亡受体1 /
- T细胞免疫球蛋白和ITIM结构域
Abstract: Objective To investigate the expression and clinical significance of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain(TIGIT) and programmed cell death protein 1(PD-1) on T follicular helper cells(Tfh) in peripheral blood of patients with chronic lymphocytic leukemia(CLL).Methods The percentage of peripheral blood Tfh cells and the levels of PD-1 and TIGIT were measured by flow cytometry in 50 CLL patients, 36 chronic B lymphocyte proliferation disease patients without CLL, and 30 healthy individuals. The differences among the three groups of subjects were compared. The percentage of TIGIT+PD-1+Tfh cells in CLL patients was analyzed in relation to IPI score stratification, as well as correlation with immunoglobulins.Results ① Compared with healthy controls, the percentages of Tfh, PD-1+Tfh, TIGIT+Tfh, TIGIT+PD-1+Tfh, TIGIT+PD-1-Tfh and TIGIT-PD-1+Tfh cells were significantly higher in newly diagnosed CLL patients(P < 0.05). ②The results of comparative analysis of TIGIT+PD-1+Tfh cells in CLL-IPI prognostic stratification low-risk, intermediate-risk, high-risk, and very high-risk groups showed that there were significant differences between and within groups(P < 0.05), and TIGIT+PD-1+Tfh cell levels gradually increased with increasing prognostic stratification. ③The results of receiver operating characteristic curve showed that TIGIT+PD-1+Tfh cells had certain diagnostic value in the differential diagnosis of CLL patients and non-CLL patients(P < 0.05). ④Logistic regression analysis showed that the percentage of TIGIT+PD-1+Tfh cells was an independent risk factor for CLL(P < 0.05). ⑤TIGIT+PD-1+Tfh was negatively correlated with IgA, IgM, and IgG levels in the peripheral blood of CLL patients(P < 0.05).Conclusion The percentage of TIGIT+PD-1+Tfh cells in peripheral blood of newly diagnosed CLL patients is significantly increased. TIGIT and PD-1, which are highly expressed in Tfh cells, are involved in the occurrence of CLL diseases and are associated with decreased immunoglobulin levels in the diseases. -
-
表 1 CLL患者组与非CLL患者组基线临床特征比较
X±S 临床特征 CLL患者组(50例) 非CLL患者组(36例) P 男∶女/例 31∶19 22∶14 0.86 年龄/岁 64.33±7.29 62.89±7.03 0.43 白细胞计数/(×109/L) 34.50±20.89 31.23±18.66 0.09 血红蛋白/(g/L) 112±23 109±25 0.10 血小板计数/(×109/L) 137±41 126±45 0.07 淋巴细胞比例/% 86±24 83±21 0.62 
下载: 导出CSV
表 2 TIGIT+PD-1+Tfh细胞、TIGIT+PD-1-Tfh细胞和TIGIT-PD-1+Tfh细胞百分比预测诊断CLL的效能
检测指标 临界值/% AUC(95%CI) 灵敏度/% 特异度/% P TIGIT+PD-1+Tfh 21.20 0.895 3(0.827 6~0.963 1) 88.79 76.67 < 0.001 TIGIT-PD-1+Tfh 6.825 0.700 0(0.587 5~0.812 5) 62.05 80.33 < 0.001 TIGIT+PD-1-Tfh 23.28 0.666 7(0.547 0~0.786 3) 58.23 76.67 0.013
下载: 导出CSV
表 3 TIGIT+PD-1+Tfh细胞和TIGIT-PD-1+Tfh细胞百分比预测鉴别诊断CLL和非CLL的效能
检测指标 临界值/% AUC(95%CI) 灵敏度/% 特异度/% P TIGIT+PD-1+Tfh 24.21 0.860 0(0.780 6~0.939 4) 74.0 92.5 < 0.001 TIGIT-PD-1+Tfh 6.978 0.658 5(0.542 0~0.775 0) 67.5 82.0 0.010
下载: 导出CSV
表 4 Logistic回归分析CLL相关的危险因素
检测指标 单因素分析 多因素分析 OR B 95%CI P OR B 95%CI P TIGIT+Tfh 1.062 0.056 1.023~1.229 0.018 1.032 0.031 0.854~1.153 0.373 PD-1+Tfh 1.116 0.059 1.006~1.128 0.038 1.090 0.087 0.873~1.239 0.154 TIGIT+PD-1+Tfh 1.440 0.337 1.254~1.713 < 0.001 1.401 0.365 1.216~1.720 < 0.001 TIGIT+PD-1-Tfh 1.147 0.220 1.033~1.289 0.014 1.038 0.037 0.898~1.202 0.613 TIGIT-PD-1+Tfh 1.260 0.057 1.050~1.845 0.030 1.169 0.219 0.903~2.346 0.079
下载: 导出CSV
-
[1] Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures[J]. Am J Hematol, 2021, 96(12): 1679-1705. doi: 10.1002/ajh.26367
[2] 罗菁, 张佼佼, 张兴利, 等. 利妥昔单抗减量的FCR方案一线治疗慢性淋巴细胞白血病疗效分析[J]. 临床血液学杂志, 2022, 35(9): 645-649. https://lcxy.whuhzzs.com/article/doi/10.13201/j.issn.1004-2806.2022.09.008
[3] Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia[J]. J Hematol Oncol, 2021, 14(1): 69. doi: 10.1186/s13045-021-01054-w
[4] De Giglio A, Di Federico A, Nuvola G, et al. The Landscape of Immunotherapy in Advanced NSCLC: Driving Beyond PD-1/PD-L1 Inhibitors(CTLA-4, LAG3, IDO, OX40, TIGIT, Vaccines)[J]. Curr Oncol Rep, 2021, 23(11): 126. doi: 10.1007/s11912-021-01124-9
[5] Liu L, Wang A, Liu X, et al. Blocking TIGIT/CD155 signalling reverses CD8(+)T cell exhaustion and enhances the antitumor activity in cervical cancer[J]. J Transl Med, 2022, 20(1): 280. doi: 10.1186/s12967-022-03480-x
[6] Yi M, Zheng X, Niu M, et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions[J]. Mol Cancer, 2022, 21(1): 28. doi: 10.1186/s12943-021-01489-2
[7] Esen F, Deniz G, Aktas EC. PD-1, CTLA-4, LAG-3, and TIGIT: The roles of immune checkpoint receptors on the regulation of human NK cell phenotype and functions[J]. Immunol Lett, 2021, 240: 15-23. doi: 10.1016/j.imlet.2021.09.009
[8] Liu G, Zhang Q, Yang J, et al. Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis[J]. Cancer Immunol Immunother, 2022, 71(2): 277-287. doi: 10.1007/s00262-021-02978-5
[9] Olatunde AC, Hale JS, Lamb TJ. Cytokine-skewed Tfh cells: functional consequences for B cell help[J]. Trends Immunol, 2021, 42(6): 536-550. doi: 10.1016/j.it.2021.04.006
[10] Le Saos-Patrinos C, Loizon S, Zouine A, et al. Elevated levels of circulatory follicular T helper cells in chronic lymphocytic leukemia contribute to B cell expansion[J]. J Leukoc Biol, 2023, 113(3): 305-314. doi: 10.1093/jleuko/qiad006
[11] Godefroy E, Zhong H, Pham P, et al. TIGIT-positive circulating follicular helper T cells display robust B-cell help functions: potential role in sickle cell alloimmunization[J]. Haematologica, 2015, 100(11): 1415-1425. doi: 10.3324/haematol.2015.132738
[12] Chu X, Tian W, Wang Z, et al. Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials[J]. Mol Cancer, 2023, 22(1): 93. doi: 10.1186/s12943-023-01800-3
[13] Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL[J]. Blood, 2018, 131(25): 2745-2760. doi: 10.1182/blood-2017-09-806398
[14] 沈悌, 赵永强. 血液病诊断及疗效标准[M]. 4版. 北京: 科学出版社, 2018: 978-979.
[15] Lu J, Wu J, Mao L, et al. Revisiting PD-1/PD-L pathway in T and B cell response: Beyond immunosuppression[J]. Cytokine Growth Factor Rev, 2022, 67: 58-65. doi: 10.1016/j.cytogfr.2022.07.003
[16] Tambunan BA, Ugrasena I, Aryati. Role of Hemin in the Immune Response of T Follicular Helper Lymphocytes Expressing T-Cell Immunoreceptor with Immunoglobulin and Immunoreceptor Tyrosine-Based Inhibitory Domains, Programmed Cell Death-1, and Interleukin-21 in Allo-Auto Positive and Negative Thalassemia[J]. J Blood Med, 2023, 14: 7-17. doi: 10.2147/JBM.S393134
[17] Ma CS, Uzel G, Tangye SG. Human T follicular helper cells in primary immunodeficiencies[J]. Curr Opin Pediatr, 2014, 26(6): 720-726. doi: 10.1097/MOP.0000000000000157
[18] Watanabe T. The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential[J]. Int J Mol Sci, 2021, 22(10): 5352. doi: 10.3390/ijms22105352
[19] Yang R, Sun L, Li CF, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy[J]. Nat Commun, 2021, 12(1): 832. doi: 10.1038/s41467-021-21099-2
[20] Ziegler AE, Fittje P, Muller LM, et al. The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56(bright)NK cells[J]. Front Immunol, 2023, 14: 1117320. doi: 10.3389/fimmu.2023.1117320
[21] Hartigan CR, Tong KP, Liu D, et al. TIGIT agonism alleviates costimulation blockade-resistant rejection in a regulatory T cell-dependent manner[J]. Am J Transplant, 2023, 23(2): 180-189. doi: 10.1016/j.ajt.2022.12.011
[22] Li X, Wang R, Fan P, et al. A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer[J]. Front Oncol, 2019, 9: 1066. doi: 10.3389/fonc.2019.01066
[23] Zou Y, Ye F, Kong Y, et al. The Single-Cell Landscape of Intratumoral Heterogeneity and The Immunosuppressive Microenvironment in Liver and Brain Metastases of Breast Cancer[J]. Adv Sci(Weinh), 2023, 10(5): e2203699.
[24] Banta KL, Xu X, Chitre AS, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8(+)T cell responses[J]. Immunity, 2022, 55(3): 512-526. doi: 10.1016/j.immuni.2022.02.005
[25] Wang M, Bu J, Zhou M, et al. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia(AML)patients[J]. Clin Immunol, 2018, 190: 64-73. doi: 10.1016/j.clim.2017.08.021
[26] Josefsson SE, Huse K, Kolstad A, et al. T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling[J]. Clin Cancer Res, 2018, 24(4): 870-881. doi: 10.1158/1078-0432.CCR-17-2337
[27] 黄自坤, 张露, 李雪, 等. 类风湿关节炎患者外周血TFH细胞TIGIT和PD1表达及意义[J]. 安徽医科大学学报, 2023, 58(5): 838-844. https://www.cnki.com.cn/Article/CJFDTOTAL-YIKE202305022.htm
[28] Arruga F, Gyau BB, Iannello A, et al. Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions[J]. Int J Mol Sci, 2020, 21(5): 1825. doi: 10.3390/ijms21051825
[29] Jain N, Senapati J, Thakral B, et al. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL[J]. Blood Adv, 2023, 7(10): 1958-1966. doi: 10.1182/bloodadvances.2022008790
[30] Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL[J]. Blood, 2017, 129(26): 3419-3427. doi: 10.1182/blood-2017-02-765685
[31] Arruga F, Rubin M, Papazoglou D, et al. The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy[J]. Haematologica, 2023, 108(8): 2101-2115. doi: 10.3324/haematol.2022.282177
[32] Brusa D, Serra S, Coscia M, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia[J]. Haematologica, 2013, 98(6): 953-963. doi: 10.3324/haematol.2012.077537
[33] Catakovic K, Gassner FJ, Ratswohl C, et al. TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia[J]. Oncoimmunology, 2017, 7(1): e1371399.
[34] Wu X, Fajardo-Despaigne JE, Zhang C, et al. Altered T Follicular Helper Cell Subsets andFunction in Chronic Lymphocytic Leukemia[J]. Front Oncol, 2021, 11: 674492. doi: 10.3389/fonc.2021.674492
[35] 朱华渊, 王莉, 乔佳, 等. CLL-IPI评分系统在中国慢性淋巴细胞白血病患者中的预后评估价值[J]. 中华血液学杂志, 2018, 39(5): 392-397.
[36] Teh BW, Tam CS, Handunnetti S, et al. Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies[J]. Blood Rev, 2018, 32(6): 499-507. doi: 10.1016/j.blre.2018.04.007
[37] Li H, Zhao A, Li M, et al. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy[J]. Front Immunol, 2022, 13: 1046755. doi: 10.3389/fimmu.2022.1046755
[38] Simon S, Voillet V, Vignard V, et al. PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy[J]. J Immunother Cancer, 2020, 8(2): e001631. doi: 10.1136/jitc-2020-001631
-
图(5)
表(4)
计量
- 文章访问数: 434
- PDF下载数: 30
- 施引文献: 0