Reduction of Regulatory T Cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sezary Syndrome
Reduction of Regulatory T Cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sezary Syndrome
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DOI：
10.1158/1078-0432.ccr-14-0830
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发表时间：
2015-01-15
影响因子：
11.5
通讯作者：
Duvic, Madeleine A.
中科院分区：
文献类型：
--
作者：
Ni, Xiao;Jorgensen, Jeffrey L.;Duvic, Madeleine A.
目的：CC趋化因子受体4 （CCR4）在皮肤T细胞淋巴瘤（CTCL）的恶性T细胞和调节性T细胞（Treg）上表达。mogamulizumab是一种去聚焦的单克隆抗体，当它与CCR4结合时，它会诱导抗体依赖性细胞对CCR4恶性T细胞产生细胞毒性。这项研究的目的是确定mogamulizumab对CTCL患者CCR4_ Tregs的影响。实验设计：通过流式细胞术分析24例参加I/II期临床试验的CTCL患者外周血中不同t细胞亚群的CCR4表达情况，在一个疗程的mogamulizumab治疗前后。分析了自然杀伤细胞（NK）的数量和功能。通过免疫组织化学检测病变组织CCR4、Foxp3和CD16的表达。结果：基线时外周血恶性T细胞CCR4阳性率为20.8%100%。14例在血液中获得应答的患者在恶性T细胞上有高基线CCR4表达。血液中的treg在基线时CCR4阳性58.6%至100%，治疗后CCR4的数量和表达下降。血液中CD8_ T细胞CCR4在基线时呈3.2% ~ 23.2%阳性，治疗后随着CD8_ T细胞百分比的增加，CCR4表达有有限的降低。在14名接受NK细胞检测的患者中，有10名患者在治疗后NK细胞的百分比有所增加。6例患者中有4例显示NK细胞毒性增加。18例基线病灶CCR4_淋巴细胞患者中有16例在治疗后计数下降。结论：Mogamulizumab降低CTCL患者的CCR4_恶性T细胞和CCR4_ Tregs水平，这可能反过来改善免疫谱。(c) 2014年aacr。
Purpose: The CC chemokine receptor 4 (CCR4) is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells (Treg). When mogamulizumab, a defucosylated monoclonal antibody, binds to CCR4, it induces antibody- dependent cellular cytotoxicity against CCR4_ malignant T cells. The goal of this study was to determine the effect of mogamulizumab on CCR4_ Tregs in patients with CTCL. Experimental Design: Peripheral blood of 24 patients with CTCL participating in a phase I/II trial was analyzed for CCR4 expression on different T-cell subsets by flow cytometry, before and after one course of mogamulizumab. The number and function of natural killer (NK) cells were also analyzed. Lesional biopsies were examined for CCR4, Foxp3, and CD16 expression by immunohistochemistry. Results: Malignant T cells in peripheral blood were 20.8%100% positive for CCR4 at baseline. Fourteen patients who achieved a response in blood had high baseline CCR4 expression on malignant T cells. Tregs in blood were 58.6% to 100% positive for CCR4 at baseline and showed decreased numbers and CCR4 expression after treatment. CD8_ T cells in blood were 3.2% to 23.2% positive for CCR4 at baseline and showed limited reduction of CCR4 expression with increased percentages of CD8_ T cells after treatment. Of 14 patients tested for NK cells in blood, 10 showed increased percentages after treatment. Four of 6 patients tested showed increased NK cell cytotoxicity. Sixteen of 18 patients who had CCR4_ lymphocytes in baseline lesions showed decreased numbers after treatment. Conclusions: Mogamulizumab reduces levels of CCR4_ malignant T cells and also CCR4_ Tregs in patients with CTCL, which may in turn improve immune profiles. (C) 2014 AACR.