調(diào)節(jié)性T細(xì)胞（Tregs）通過(guò)防止免疫細(xì)胞攻擊自身機(jī)體對(duì)于人體健康有著重要作用,。但是,，在腫瘤微環(huán)境中Tregs細(xì)胞卻抑制針對(duì)腫瘤細(xì)胞的免疫反應(yīng),。由于Tregs 細(xì)胞表面表達(dá)CD25,，Rech等人認(rèn)為針對(duì)CD25的單抗免疫抑制藥物daclizumab也許可以清除Tregs 細(xì)胞,，從而恢復(fù)抗腫瘤免疫反應(yīng),。
他們的假說(shuō)得到了證實(shí),。5月16日國(guó)際著名轉(zhuǎn)化醫(yī)學(xué)雜志Science Translational Medicine發(fā)表了他們的研究論文“CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients”,。
文章報(bào)道，daclizumab在體外實(shí)驗(yàn)中可使Tregs 細(xì)胞失去免疫抑制和分泌γ干擾素的功能,。這一轉(zhuǎn)變與向效應(yīng)性T細(xì)胞轉(zhuǎn)變的表型一致,。研究者進(jìn)而給轉(zhuǎn)移性乳腺癌患者同時(shí)使用daclizumab和實(shí)驗(yàn)性腫瘤疫苗。結(jié)果發(fā)現(xiàn),，這些患者具有更低的Tregs 細(xì)胞數(shù)目和更高水平的疫苗抗原特異性效應(yīng)T細(xì)胞免疫反應(yīng),。盡管減少了Tregs 細(xì)胞，這些患者并沒(méi)有發(fā)生自身免疫反應(yīng),。
雖然,，這項(xiàng)研究還處于初級(jí)階段，但是daclizumab在不引發(fā)自身免疫的情況下恢復(fù)抗腫瘤免疫反應(yīng)的前景,，仍然備受期待,。(生物谷Bioon.com)
DOI:10.1126/scitranslmed.3003330
PMC:
PMID:
CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients
Andrew J.Rech， Rosemarie Mick,， Sunil Martin1,， Adri Recio,， Nicole A. Aqui， Daniel J. Powell Jr.,， Theresa A. Colligon1,， Jennifer A. Trosko1， Leah I. Leinbach,， Charles H. Pletcher,， Carol K. Tweed， Angela DeMichele,， Kevin R. Fox,， Susan M. Domchek， James L. Riley,，and Robert H. Vonderheide
Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance,， but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro， daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover,， daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-γ,， consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo， we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.
