Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy ; Ludwig Center for Cancer Research of the University of Lausanne, 1011 Lausanne, Switzerland.
Department of Specialistic, Diagnostic and Experimental Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, 40138 Bologna, Italy.
J Immunol Res. 2015;2015:253191. doi: 10.1155/2015/253191. Epub 2015 Feb 26.
In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2.
在过去的几年中，树突状细胞（DC）已被评估用于抗肿瘤疫苗接种。尽管基于 DC 的疫苗带来了很高的期望，但它们的临床转化却令人大失所望。对于这些结果，已经提出了几种解释。特别是，已经证明了 DC 同时表达了耐受性途径，例如免疫抑制剂吲哚胺 2,3-双加氧酶-1（IDO1）。本研究旨在评估 PGE2 成熟后单核细胞来源的 DC（Mo-DC）的刺激和耐受性特征。特别是，已经解决了 IDO1 表达在 PGE2 成熟的 Mo-DC 中的作用。在这里，我们表明 PGE2 是 DC 完全成熟所必需的，它通过增强 IDO1 成为 DC 耐受性的一种介质。PGE2 介导的 IDO1 表达导致犬尿氨酸的产生，Treg 的产生以及 DC 的同种异体或自体抗原特异性刺激能力的抑制。当用白血病裂解物脉冲并成熟 PGE2 时，由于 IDO1 的上调，DC 在诱导 IFN-γ分泌的 CD4（+）和 CD8（+）T 细胞方面受到损害。此外，IDO1 的抑制增强了抗白血病反应。总的来说，这些结果表明使用 IDO1 抑制剂来增强用 PGE2 成熟的 DC 的疫苗接种能力。
