CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
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DOI：
10.1126/scitranslmed.3003330
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发表时间：
2012-05-16
影响因子：
17.1
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Rech AJ;Mick R;Martin S;Recio A;Aqui NA;Powell DJ Jr;Colligon TA;Trosko JA;Leinbach LI;Pletcher CH;Tweed CK;DeMichele A;Fox KR;Domchek SM;Riley JL;Vonderheide RH
调节性T细胞（Tcells）是免疫耐受的关键介质，在癌症中表现突出。体内CD25 + FoxP3 + T细胞的耗竭可能会促进T细胞癌的免疫监视，但在人类中没有这样做的策略，同时保留免疫力和预防自身免疫已经得到验证。我们评估了食品和药物管理局批准的CD25阻断单克隆抗体daclizumab对人Treg存活和功能的影响。在体外，daclizumab不介导抗体依赖性或补体介导的细胞毒性，而是导致FoxP3选择性下调CD25high CD45RAneg T细胞。此外，达克珠单抗治疗的CD45RAneg TcR丧失了抑制功能，并恢复了产生干扰素-γ的能力，与重编程一致。为了了解daclizumab在体内对TcB的影响，我们在转移性乳腺癌患者中进行了daclizumab与实验性癌症疫苗联合的临床试验。达克珠单抗给药导致患者的TdR显著和长期降低。在不存在自身免疫的情况下，观察到针对所有疫苗抗原的稳健的CD8和CD4 T细胞引发和加强。我们的结论是，CD25阻断耗尽和选择性地重新编程TcR在音乐会与积极的免疫治疗癌症患者。这些结果表明了一种靶向癌症相关性T细胞同时避免自身免疫的机制。
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.
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影响因子：
15.3
作者：
Bayer, AL;Yu, AX;Adeegbe, D;Malek, TR
通讯作者：
Malek, TR
DOI：
10.4049/jimmunol.181.4.2855
发表时间：
2008-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Golovina TN;Mikheeva T;Suhoski MM;Aqui NA;Tai VC;Shan X;Liu R;Balcarcel RR;Fisher N;Levine BL;Carroll RG;Warner N;Blazar BR;June CH;Riley JL
通讯作者：
Riley JL
DOI：
10.1073/pnas.0601335103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Bielekova, B;Catalfamo, M;Martin, R
通讯作者：
Martin, R
DOI：
10.1073/pnas.0402653101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Bielekova, B;Richert, N;Martin, R
通讯作者：
Martin, R
DOI：
10.1111/j.1749-6632.2009.04939.x
发表时间：
2009-01-01
期刊：
CANCER VACCINES
影响因子：
--
作者：
Rech, Andrew J.;Vonderheide, Robert H.
通讯作者：
Vonderheide, Robert H.