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The OX40-OX40L molecule system in leukemia: Expression, function and modulation of NK cell reactivity

白血病中的 OX40-OX40L 分子系统：NK 细胞反应性的表达、功能和调节

基本信息

批准号：
244459007
负责人：
Dr. Tina Nuebling
金额：
--
依托单位：
Universitätsklinik für Kinder- und Jugendmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/244459007?language=en
关键词：
OX40 OX40L molecule system leukemia

项目摘要

NK cells play an important role in the immunosurveillance of malignancies, especially in leukemia. Their reactivity is guided by a balance of signals from a variety of activating and inhibitory receptors, and several members of the TNF family contribute to the same. In general, many molecules of the TNF family play an important role in the activation, proliferation, and apoptosis of both tumor and immune effector cells. Other investigators reported recently, that upon activation NK cells can express the TNF family member OX40 ligand (OX40L), which primarily is known to be expressed by antigen presenting cells (APC), where it serves as ligand for OX40 on T cells. Alike many other ligands of the TNF family, OX40L is capable to transduce bidirectional signals, and such reverse signaling via OX40L was found to affect the immunomodulatory properties of APC. The functional role of OX40L on NK cells in general and their interaction with tumor cells in particular is yet unknown. In the preliminary work for this project we found that polyklonal NK cells, generated by different protocols for clinical use in adoptive transfer to cancer patients, differentially express OX40L. Signaling via OX40L into NK cells led to activation (upregulation of CD69 and NKp44) and enhanced IFN-gamma production of the NK cells. Furthermore, we already generated and functionally characterized monoclonal antibodies against the cognate receptor OX40. Using these antibodies we could show that OX40 is expressed in a high percentage on patient leukemia cells, predominantly in AML. Stimulation of OX40 lead to release of pathophysiologically relevant cytokines and increased metabolic activity of the leukemia cells. With regard to the functional relevance of the molecule system in the immunosurveillance of malignant cells by NK cells, further preliminary data revealed that OX40-OX40L interaction increased the reactivity of NK cells against target cells.The proposed project now aims to comprehensively analyze the expression of OX40 in a larger cohort of samples from patients with various leukemia entities, and also its suitability as a prognostic marker in the disease. Furthermore we plan to study whether and how OX40 affects proliferation, apoptosis, cytokine production and immunogenicity of leukemia cells. Finally, the influence of OX40L on the reactivity of NK cells will be thoroughly examined with particular emphasis on its role in their interaction with malignant hematopoietic cells. The overall objective of this project thus is to characterize the function of OX40 and its ligand in NK cell immunosurveillance of leukemia cells with the aim of a potential therapeutic modulation in patients.

NK细胞在恶性肿瘤的免疫监视中发挥着重要作用，特别是在白血病中。它们的反应性由多种激活和抑制受体的信号平衡引导，TNF 家族的几个成员也对此做出了贡献。一般来说，TNF家族的许多分子在肿瘤和免疫效应细胞的激活、增殖和凋亡中发挥重要作用。其他研究人员最近报道，NK 细胞激活后可以表达 TNF 家族成员 OX40 配体 (OX40L)，已知该配体主要由抗原呈递细胞 (APC) 表达，在抗原呈递细胞中充当 T 细胞上 OX40 的配体。与 TNF 家族的许多其他配体一样，OX40L 能够转导双向信号，并且发现通过 OX40L 的这种反向信号传导会影响 APC 的免疫调节特性。 OX40L 对 NK 细胞的总体功能作用以及它们与肿瘤细胞的相互作用尚不清楚。在该项目的前期工作中，我们发现通过不同方案产生的多克隆 NK 细胞，用于临床过继转移给癌症患者，其 OX40L 表达存在差异。通过 OX40L 向 NK 细胞发出信号，导致 NK 细胞激活（CD69 和 NKp44 上调）并增强 IFN-γ 的产生。此外，我们已经生成了针对同源受体 OX40 的单克隆抗体并进行了功能表征。使用这些抗体，我们可以证明 OX40 在患者白血病细胞（主要是 AML）中以高百分比表达。 OX40 的刺激导致病理生理学相关细胞因子的释放并增加白血病细胞的代谢活性。关于该分子系统在 NK 细胞对恶性细胞免疫监视中的功能相关性，进一步的初步数据显示 OX40-OX40L 相互作用增加了 NK 细胞对靶细胞的反应性。该项目现在旨在全面分析 OX40 在来自各种白血病患者的更大样本群中的表达，以及其作为预后标志物的适用性。疾病。此外，我们计划研究 OX40 是否以及如何影响白血病细胞的增殖、凋亡、细胞因子产生和免疫原性。最后，将彻底检查 OX40L 对 NK 细胞反应性的影响，特别强调其在 NK 细胞与恶性造血细胞相互作用中的作用。因此，该项目的总体目标是表征 OX40 及其配体在白血病细胞 NK 细胞免疫监视中的功能，旨在对患者进行潜在的治疗调节。