Liu Shanrong, Foster Barbara A, Chen Tie, Zheng Guoxing, Chen Aoshuang
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois 61107, USA.
Clin Cancer Res. 2007 Jan 1;13(1):283-91. doi: 10.1158/1078-0432.CCR-06-1913.
The modification of therapeutic dendritic cells (DC) with various immunostimulatory molecules represents a useful means for improving the antitumor efficacy of DC transfer-based immunotherapy. We have evaluated the feasibility of modifying therapeutic DCs with multiple immunostimulatory molecules using a time-efficient, protein transfer (or protein "painting")-based method.
Bone marrow-derived DCs were painted with either control protein human IgG (hIgG) or three immunostimulatory molecules, SLC, 4-1BBL, and TRANCE (the triad protein). Painted DCs were injected intratumorally into mice bearing established tumors. Subsequently, the capacities of painted DCs to migrate to the draining lymph nodes, recruit the host T cells, promote Th1 cytokine responses, and elicit therapeutic antitumor responses were evaluated.
The triad protein transfer yields a uniform population of DCs that coexpress all three of the proteins. Compared with the hIgG-painted DCs, the triad protein-painted DCs migrate more efficiently to the draining lymph nodes and show enhanced capabilities to induce T cell infiltration of tumors and to promote Th1 cytokine responses in vivo. Furthermore, in both the EG.7 and TRAMP-C2 tumor models, compared with the DCs painted with hIgG or only one of the three proteins, the triad protein-painted DCs, upon adoptive transfer, elicit stronger therapeutic responses against established tumors. Importantly, the antitumor responses of the triad protein-painted DCs are mediated by systemic antitumor immunity.
This study establishes, for the first time, the feasibility of optimizing DC transfer-based immunotherapy via combinatorial protein transfer of therapeutic DCs with an array of immunostimulatory molecules.
用各种免疫刺激分子修饰治疗性树突状细胞（DC）是提高基于DC转移的免疫治疗抗肿瘤疗效的一种有用方法。我们已经评估了使用一种省时的、基于蛋白质转移（或蛋白质“绘画”）的方法用多种免疫刺激分子修饰治疗性DC的可行性。
用对照蛋白人IgG（hIgG）或三种免疫刺激分子SLC、4-1BBL和TRANCE（三联蛋白）对骨髓来源的DC进行“绘画”。将“绘画”后的DC瘤内注射到已建立肿瘤的小鼠体内。随后，评估“绘画”后DC迁移至引流淋巴结、募集宿主T细胞、促进Th1细胞因子反应以及引发治疗性抗肿瘤反应的能力。
三联蛋白转移产生了均匀的DC群体，这些DC共表达所有三种蛋白质。与hIgG“绘画”的DC相比，三联蛋白“绘画”的DC更有效地迁移至引流淋巴结，并在体内表现出更强的诱导肿瘤T细胞浸润和促进Th1细胞因子反应的能力。此外，在EG.7和TRAMP-C2肿瘤模型中，与用hIgG或三种蛋白质之一“绘画”的DC相比，三联蛋白“绘画”的DC在过继转移后对已建立的肿瘤引发更强的治疗反应。重要的是，三联蛋白“绘画”的DC的抗肿瘤反应是由全身抗肿瘤免疫介导的。
本研究首次证实了通过将治疗性DC与一系列免疫刺激分子进行组合蛋白质转移来优化基于DC转移的免疫治疗的可行性。
