Increase of Circulating CD4+CD25highFoxp3+ Regulatory T Cells in Patients With Metastatic Renal Cell Carcinoma During Treatment With Dendritic Cell Vaccination and Low-Dose Interleukin-2
Increase of Circulating CD4+CD25highFoxp3+ Regulatory T Cells in Patients With Metastatic Renal Cell Carcinoma During Treatment With Dendritic Cell Vaccination and Low-Dose Interleukin-2
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DOI：
10.1097/cji.0b013e3181cd870f
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发表时间：
2010-05-01
影响因子：
3.9
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
--
作者：
Berntsen, Annika;Brimnes, Marie Klinge;Svane, Inge Marie
调节性T细胞（Regulatory T cells, Treg）在维持免疫耐受中起着重要作用，可能是肿瘤免疫治疗成功的障碍之一。在这项研究中，我们分析了转移性肾癌患者树突状细胞（DC）疫苗联合低剂量白细胞介素(IL)-2对外周血CD4(+) CD25（高）Foxp3(+) Treg细胞频率的影响。我们发现，与预处理水平相比，治疗使Treg细胞的频率增加了7倍以上（P < 0.0001）。当患者停止IL-2治疗仅8天时，Treg细胞的频率下降，但仍高于预处理水平。功能分析表明，分离的Treg细胞能够抑制应答细胞的增殖。此外，体外研究表明，成熟dc、自体T细胞和IL-2共培养可导致Treg细胞数量增加，而IL-21不会刺激Treg细胞的诱导。这些发现表明，即使是低剂量的IL-2联合DC疫苗接种，也能够在转移性肾癌患者体内扩增CD4(+)CD25(+)Foxp3(+) Treg细胞。此外，研究结果表明，IL-2对Treg细胞的诱导作用是可逆的，并且在IL-2治疗终止后不久就会下降。我们的数据表明，结合dc介导的免疫治疗和Treg细胞消耗的方法可能是必要的，以增强疫苗治疗的能力，从而在癌症患者中引发有效的抗肿瘤反应。此外，佐剂给予IL-21可能导致免疫增强，而不同时诱导Treg细胞。
Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2 in patients with metastatic renal cell carcinoma on the frequency of CD4(+) CD25(high)Foxp3(+) Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P < 0.0001). The frequency of Treg cells decreased when patients had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads to an increase in the number of Treg cells whereas IL-21 does not stimulate the induction of Treg cells. These findings demonstrate that even low doses of IL-2 in combination with DC vaccination are able to expand CD4(+)CD25(+)Foxp3(+) Treg cells in vivo in metastatic renal cell carcinoma patients. Further, the results indicate that the IL-2-induced effect on Treg cells is reversible and declines shortly after termination of IL-2 treatment. Our data suggest that approaches combining DC-mediated immunotherapy and depletion of Treg cells may be necessary to enhance the ability of vaccination therapy to elicit effective antitumor responses in cancer patients. Also, adjuvant IL-21 administration may lead to immune enhancement without simultaneous induction of Treg cells.