Vujanovic L, Ranieri E, Gambotto A, Olson W C, Kirkwood J M, Storkus W J
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Cancer Gene Ther. 2006 Aug;13(8):798-805. doi: 10.1038/sj.cgt.7700964. Epub 2006 Apr 28.
Although CD4(+) Type-1T helper (Th1) cells secreting interferon-gamma (IFN-gamma) appear to play an essential role in promoting durable antitumor immunity, we have previously shown that patients with cancer exhibit dysfunctional Th1-type responses against epitopes derived from tumor antigens, such as MAGE-A6. Here, we engineered human dendritic cells (DCs) to secrete high levels of the IFN-gamma-inducing cytokines, interleukin (IL)-12p70 and IL-18, via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12/18) were more effective at stimulating MAGE-A6-specific Th1-type CD4(+) T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Psi5 virus or uninfected DCs. Furthermore, we show that DC.IL-12/18 loaded with recombinant MAGE-A6 protein (rMAGE) and used as in vitro stimulators promote Th1-type immunity that is frequently directed against multiple MAGE-A6-derived epitopes. The superiority of DC.IL-12/18-based stimulations in melanoma patients was independent of disease stage or current disease status. Based on these results, we believe this modality may prove clinically useful as a vaccine platform to promote the recovery of tumor antigen-specific, Th1-type CD4(+) T-cell responses in patients with cancer.
尽管分泌干扰素-γ（IFN-γ）的CD4(+) 1型辅助性T细胞（Th1）似乎在促进持久抗肿瘤免疫中发挥着关键作用，但我们之前已经表明，癌症患者对源自肿瘤抗原（如MAGE-A6）的表位表现出功能失调的Th1型反应。在此，我们通过重组腺病毒感染对人树突状细胞（DC）进行基因工程改造，使其分泌高水平的诱导IFN-γ的细胞因子白细胞介素（IL）-12p70和IL-18，以产生一种能够促进之前存在缺陷的患者Th1型反应的体外刺激物。与单独感染细胞因子载体之一、对照Ad.Psi5病毒或未感染的DC相比，共感染Ad.IL-12和Ad.IL-18的树突状细胞（DC.IL-12/18）在刺激MAGE-A6特异性Th1型CD4(+) T细胞反应方面更有效。此外，我们表明，负载重组MAGE-A6蛋白（rMAGE）并用作体外刺激物的DC.IL-12/18可促进Th1型免疫，这种免疫通常针对多个源自MAGE-A6的表位。基于DC.IL-12/18的刺激在黑色素瘤患者中的优势与疾病阶段或当前疾病状态无关。基于这些结果，我们认为这种方式可能被证明在临床上作为一种疫苗平台是有用的，以促进癌症患者肿瘤抗原特异性Th1型CD4(+) T细胞反应的恢复。
