Interferon-alpha (IFN-α)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients
Interferon-alpha (IFN-α)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients
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DOI：
10.1097/cji.0b013e318167b023
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发表时间：
2008-04-01
影响因子：
3.9
通讯作者：
Ranieri, Elena
中科院分区：
文献类型：
--
作者：
Gigante, Margherita;Mandic, Maja;Ranieri, Elena
树突状细胞（DC）是有效的抗原呈递细胞，并且代表用于肾细胞癌（RCC）患者的新型免疫疗法的有吸引力的候选者，肾细胞癌（RCC）是一种已被证明对常规治疗方式（诸如化学疗法和放射疗法）难治的疾病。考虑到增强抗肿瘤I型免疫（T（C）1和T（h）1）作为治疗终点的感知需求，以及DC群体的已知功能可塑性（其可显示促进T细胞应答的异质性能力），我们试图鉴定具有这种能力的优选DC制剂。我们比较了使用干扰素-α（IFN-α）（IFN-DC和α DCI）的单核细胞衍生DC的2种不同制备物与使用白细胞介素-1 β/白细胞介素-6/肿瘤坏死因子-α/前列腺素E-2的经典DC“成熟”（mDC），以了解其体外促进RCC患者自体T（C）1抗肿瘤反应的能力。IFN-α处理的DC在体外刺激（IVS）后比细胞因子混合物-mDC促进显著更高数量的RCC特异性CD 8（+）T细胞，其表现出细胞毒性表型。此外，使用IFN-DCs的IVS能够减少CD 4（+）T细胞应答者群体中的调节型T细胞，而使用传统的基于mDC的疫苗的IVS则相反。这些数据强调了IFN-a在调节DC的免疫功能方面的重要作用，使其成为能够协调促进T（H）1型和T（C）1型T细胞介导的免疫的极化DC 1型，并支持患者来源的IFN-a条件DC的翻译开发用于RCC患者的新型免疫疗法，其中内源性肿瘤特异性T（C）1效应细胞可能功能失调，无反应性或易于发生细胞凋亡。
Dendritic cells (DCs) are potent antigen presenting cells and represent attractive candidates for use in novel immunotherapies for patients with renal cell carcinoma (RCC), a disease that has proven refractory to conventional treatment modalities, such as chemotherapy and radiotherapy. Given the perceived need to augment antitumor type-l immunity (T(C)1 and T(h)1) as a therapeutic end point, and the known functional plasticity of DC populations that may display heterogeneous capacity to promote T-cell responses, we sought to identify a preferred DC preparation with this capacity. We compared 2 different preparations of monocyte-derived DC using interferon-alpha (IFN-alpha) (IFN-DC and alpha DCI) with classic DCs "matured" (mDCs) using interleukin-1 beta/interleukin-6/tumor necrosis factor-alpha/prostaglandin E-2, for their ability to promote autologous T(C)1 antitumor responses from RCC patients in vitro. IFN-alpha-conditioned DC promoted significantly higher numbers of RCC-specific CD8(+) T cells exhibiting a cytotoxic phenotype after in vitro stimulation (IVS) than cytokine cocktail-mDCs. Furthermore, IVS using IFN-DCs was able to diminish regulatory-type T cells among CD4(+) T-cell responder populations versus IVS using conventional mDC-based vaccines. These data emphasize an important role for IFN-a in modulating the immunologic functions of DCs toward a polarized DC1-type capable of coordinately promoting T(H)1- type and T(C)1-type T-cell mediated immunity and supports the translational development of patient-derived IFN-alpha-conditioned DC for use in novel immunotherapies for patients with RCC, and in whom, endogenous tumor-specific T(C)1 effector cells may be dysfunctional, anergic, or prone to undergo apoptosis.