Gigante Margherita, Mandic Maja, Wesa Amy K, Cavalcanti Elisabetta, Dambrosio Michele, Mancini Vito, Battaglia Michele, Gesualdo Loreto, Storkus Walter J, Ranieri Elena
Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
J Immunother. 2008 Apr;31(3):254-62. doi: 10.1097/CJI.0b013e318167b023.
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-1 immunity (TC1 and Th1) 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 alphaDC1) with classic DCs "matured" (mDCs) using interleukin-1beta/interleukin-6/tumor necrosis factor-alpha/prostaglandin E2, for their ability to promote autologous TC1 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-alpha in modulating the immunologic functions of DCs toward a polarized DC1-type capable of coordinately promoting TH1-type and TC1-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 TC1 effector cells may be dysfunctional, anergic, or prone to undergo apoptosis.
树突状细胞（DCs）是强大的抗原呈递细胞，是用于肾细胞癌（RCC）患者新型免疫疗法的有吸引力的候选者。肾细胞癌对化疗和放疗等传统治疗方式已证明具有难治性。鉴于将增强抗肿瘤1型免疫（TC1和Th1）作为治疗终点的需求，以及已知DC群体具有功能可塑性，可能表现出促进T细胞反应的异质性能力，我们试图确定具有这种能力的首选DC制剂。我们比较了使用α干扰素（IFN-α）制备的2种不同的单核细胞衍生DC（IFN-DC和αDC1）与使用白细胞介素-1β/白细胞介素-6/肿瘤坏死因子-α/前列腺素E2“成熟”的经典DC（mDCs）在体外促进RCC患者自体TC1抗肿瘤反应的能力。与细胞因子鸡尾酒诱导的mDCs相比，IFN-α预处理的DC在体外刺激（IVS）后能显著促进更多表现出细胞毒性表型的RCC特异性CD8 + T细胞。此外，与使用基于传统mDC的疫苗进行IVS相比，使用IFN-DC进行IVS能够减少CD4 + T细胞应答群体中的调节性T细胞。这些数据强调了IFN-α在将DC的免疫功能调节为能够协同促进TH1型和TC1型T细胞介导的免疫的极化DC1型中的重要作用，并支持将患者来源的IFN-α预处理的DC用于RCC患者新型免疫疗法的转化开发，在这些患者中，内源性肿瘤特异性TC1效应细胞可能功能失调、无反应或易于发生凋亡。
