Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells
Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells
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DOI：
10.1172/jci25947
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发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
Vieweg, J
中科院分区：
文献类型：
--
作者：
Dannull, J;Su, Z;Vieweg, J
在这项研究中，我们研究了使用重组IL-2白喉毒素缀合物DAB（389）IL-2（也称为地尼白介素diftitox和ONTAK）消除CD 4（+）/CD 25（+）T细胞是否能够增强肿瘤RNA转染的DC疫苗的免疫刺激功效。我们表明，DAB 389 IL-2能够选择性地消除癌症患者PBMC中表达CD 25的T细胞亚群，而不会对其他中等或低表达CD 25的细胞亚群产生毒性。DAB（389）IL-2介导的Treg耗竭导致体外增殖和细胞毒性T细胞应答的刺激增强，但仅当在T细胞引发期间省略DAB 389 IL-2时。DAB 389 IL-2显著减少了转移性肾细胞癌（RCC）患者外周血中存在的Treg的数量，并消除了Treg介导的体内免疫抑制活性。此外，与单独接种疫苗相比，DAB（389）IL-2介导的TcB消除后接种RNA转染的DC显著提高了RCC患者肿瘤特异性T细胞应答的刺激。我们的研究结果可能对设计基于免疫的策略具有影响，这些策略可能包含Treg耗竭策略以实现具有治疗影响的有效抗肿瘤免疫。
In this study, we investigated whether elimination of CD4(+)/CD25(+) Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB(389)IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB389IL-2 is capable of selectively eliminating CD25-expressing Tregs from the PBMCs of cancer patients without inducing toxicity on other cellular subsets with intermediate or low expression of CD25. DAB(389)IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB389IL-2 was omitted during T cell priming. DAB389IL-2 significantly reduced the number of Tregs present in the peripheral blood of metastatic renal cell carcinoma (RCC) patients and abrogated Treg-mediated immunosuppressive activity in vivo. Moreover, DAB(389)IL-2-mediated elimination of Tregs followed by vaccination with RNA-transfected DCs significantly improved the stimulation of tumor-specific T cell responses in RCC patients when compared with vaccination alone. Our findings may have implications in the design of immune-based strategies that may incorporate the Treg depletion strategy to achieve potent antitumor immunity with therapeutic impact.