多发性骨髓瘤患者中程序性死亡-1、含T细胞免疫球蛋白和粘蛋白结构域分子3表型的耗竭性CD8 T细胞增加。
Increased exhausted CD8 T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma.
作者信息
Tan Jiaxiong, Chen Shaohua, Huang Jingying, Chen Youchun, Yang Lijian, Wang Chunli, Zhong Jun, Lu Yuhong, Wang Liang, Zhu Kanger, Li Yangqiu
机构信息
Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China.
Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, China.
出版信息
Asia Pac J Clin Oncol. 2018 Oct;14(5):e266-e274. doi: 10.1111/ajco.13033. Epub 2018 Jun 25.
AIM
The immunosuppressive microenvironment plays a crucial role in T-cell immunodeficiency in multiple myeloma (MM). Overexpression of T-cell immunosuppressive receptors, including programmed death-1 (PD-1) and T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3), may be related to tumor immunosuppression and poor prognosis, and the malignant bone marrow (BM) microenvironment may contribute to such immunosuppression. The purpose of this study was to analyze the distribution of PD-1 and/or Tim-3 T cells in different T-cell subset in patients with MM.
METHODS
The expression of PD-1 and Tim-3 with exhausted (CD244 and CD57 ) CD3 , CD4 and CD8 T cells between BM and peripheral blood (PB) from 10 patients with untreated MM was detected by multicolor flow cytometry assay.
RESULTS
A significant increase in both PD-1 CD57 and Tim-3 CD57 CD3 T cells and PD-1 Tim-3 CD3 T cells was detected in PB from patients with MM compared with 10 healthy individuals (HIs), and the alteration was mostly in the CD8 T-cell subset. Significant higher percentage of PD-1 CD3 T cells was found in BM compared with PB from patients with MM. The level of PD-1 Tim-3 CD3 , CD4 , and CD8 T cells was high in BM group compared with PB. Moreover, PD-1 CD244 or PD-1 CD57 CD3 T cells, particularly PD-1 CD244 and PD-1 CD57 CD8 T cells were significantly higher in BM than in PB. In addition, limited dynamic detection data from three MM cases who achieved complete remission after treatment showed that the numbers of either PD-1 or PD-1 Tim-3 T cells in different T-cell subsets were decreased in both BM and PB.
CONCLUSION
We characterized the distribution of PD-1 and TIM-3 concurrent with exhausted CD3 , CD4 and CD8 T cells between BM and PB from patients with MM. Higher numbers of PD-1 CD244 or PD-1 CD57 CD3 T cells in BM from patients with MM may contribute to mediate the BM immunosuppressive microenvironment. Although heterogeneous alterations in Tim-3 T cells may represent a complex immunosuppressive pattern in MM. Overall, higher levels of PD-1 CD244 or PD-1/Tim-3 CD57 CD8 T cells may be a major reason for lower T-cell activation and T-cell immunodeficiency in MM.
目的
免疫抑制微环境在多发性骨髓瘤（MM）的T细胞免疫缺陷中起关键作用。包括程序性死亡-1（PD-1）和含T细胞免疫球蛋白和粘蛋白结构域3（Tim-3）在内的T细胞免疫抑制受体的过表达可能与肿瘤免疫抑制及不良预后相关，而恶性骨髓（BM）微环境可能促成这种免疫抑制。本研究旨在分析MM患者不同T细胞亚群中PD-1和/或Tim-3 T细胞的分布情况。
方法
采用多色流式细胞术检测10例未经治疗的MM患者骨髓和外周血（PB）中PD-1和Tim-3与耗竭（CD244和CD57）的CD3⁺、CD4⁺和CD8⁺ T细胞的表达。
结果
与10名健康个体（HI）相比，MM患者PB中PD-1⁺CD57⁺和Tim-3⁺CD57⁺CD3⁺ T细胞以及PD-1⁺Tim-3⁺CD3⁺ T细胞均显著增加，且这种改变主要发生在CD8⁺ T细胞亚群中。与MM患者的PB相比，BM中PD-1⁺CD3⁺ T细胞的百分比显著更高。与PB相比，BM组中PD-1⁺Tim-3⁺CD3⁺、CD4⁺和CD8⁺ T细胞水平较高。此外，BM中PD-1⁺CD244或PD-1⁺CD57⁺CD3⁺ T细胞，尤其是PD-1⁺CD244和PD-1⁺CD57⁺CD8⁺ T细胞显著高于PB。另外，来自3例治疗后达到完全缓解的MM病例的有限动态检测数据显示，不同T细胞亚群中PD-1或PD-1⁺Tim-3⁺ T细胞的数量在BM和PB中均减少。
结论
我们对MM患者骨髓和外周血中与耗竭的CD3⁺、CD4⁺和CD8⁺ T细胞同时存在的PD-1和TIM-3的分布进行了表征。MM患者骨髓中较高数量的PD-1⁺CD244或PD-1⁺CD57⁺CD3⁺ T细胞可能有助于介导骨髓免疫抑制微环境。尽管Tim-3 T细胞的异质性改变可能代表MM中一种复杂的免疫抑制模式。总体而言，较高水平的PD-1⁺CD244或PD-1/Tim-3⁺CD57⁺CD8⁺ T细胞可能是MM中T细胞活化降低和T细胞免疫缺陷的主要原因。
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