A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor microenvironment.
A therapeutic OX40 agonist dynamically alters dendritic, endothelial, and T cell subsets within the established tumor microenvironment.
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DOI：
10.1158/0008-5472.can-10-1369
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Pardee AD;McCurry D;Alber S;Hu P;Epstein AL;Storkus WJ
目前几乎没有临床前模型支持将0X 40激动剂用作晚期癌症背景中的治疗剂，以及通过其实现治疗功效的机制。我们证明，用新型OX 40配体-Fc融合蛋白（OX 40 L-Fc）治疗荷有良好建立的第17天肉瘤的小鼠，导致大多数治疗动物的肿瘤消退或休眠。出乎意料的是，进行性肿瘤微环境（TME）中的树突状细胞（DC）获得0X 40表达并结合荧光标记的0X 40 L-Fc。此外，纵向分析显示，DC在OX 40 L-Fc处理后三天内在野生型和Rag-/-小鼠的肿瘤引流淋巴结（TDLN）中富集。到治疗后第7天，在TDLN中注意到CXCR 3 + T效应细胞的显著扩增，并且到治疗后第10天，显示再激活记忆表型的1型极化T细胞已经在肿瘤中积累。在用0X 40 L-Fc处理后的早期，在TME中观察到高水平的CXCL 9（CXCR 3配体）和血管内皮细胞（VEC）的VCAM-1表达增强。值得注意的是，这些血管改变在Rag-/-小鼠中得以维持，表明0X 40 L-Fc介导的DC和VEC的活化以T细胞非依赖性方式发生。总的来说，这些发现支持了一种范例，其中通过0X 40激动剂刺激DC、T细胞和肿瘤血管系统动态地协调治疗性T细胞的活化、扩增和募集到已建立的肿瘤中。
Little preclinical modeling currently exists to support the use of OX40 agonists as therapeutic agents in the setting of advanced cancers, as well as, the mechanisms through which therapeutic efficacy is achieved. We demonstrate that treatment of mice bearing well-established day 17 sarcomas with a novel OX40 ligand-Fc fusion protein (OX40L-Fc) resulted in tumor regression or dormancy in the majority of treated animals. Unexpectedly, dendritic cells (DC) in the progressive tumor microenvironment (TME) acquire OX40 expression and bind fluorescently-labeled OX40L-Fc. Furthermore, longitudinal analyses revealed that DC become enriched in the tumor-draining lymph node (TDLN) of both wild-type and Rag-/- mice within three days after OX40L-Fc treatment. By day 7 after treatment, a significant expansion of CXCR3+ T effector cells was noted in the TDLN, and by day 10 post-treatment, Type-1 polarized T cells exhibiting a re-activated memory phenotype had accumulated in the tumors. High levels of CXCL9 (a CXCR3 ligand) and enhanced expression of VCAM-1 by vascular endothelial cells (VEC) were observed in the TME early after treatment with OX40L-Fc. Notably, these vascular alterations were maintained in Rag-/- mice, indicating that the OX40L-Fc-mediated activation of both DC and VEC occur in a T cell-independent manner. Collectively, these findings support a paradigm in which the stimulation of DC, T cells and the tumor vasculature by an OX40 agonist dynamically orchestrates the activation, expansion and recruitment of therapeutic T cells into established tumors.