Targeted Modulation of the NKG2D Axis to Trigger Anti-Leukemia NK Cell and T Cell Responses

自然杀伤组2成员D （NKG2D）受体/配体轴在消除新发肿瘤细胞中起关键作用。NKG2D在癌症免疫监测中的重要作用已在各种动物模型和患者中得到支持，其中癌症发展的风险与NKG2D编码基因的特定变体相关。NKG2D识别不同的蛋白质配体，这些配体在病毒感染细胞和肿瘤细胞的细胞表面表达，并作为危险信号。对这些配体的识别触发NK细胞和T细胞的激活，并导致表达配体的细胞的消除。在进展过程中，肿瘤通过下调或脱落NKG2D配体来逃避这种识别。在AML中，白血病起始细胞已被证明缺乏NKG2D配体表达，从而逃避免疫识别。此外，在临床研究中，某些NKG2D配体的表达与总生存率的提高相关。基于RNA谱的初步研究表明，NKG2D配体在B细胞白血病中的低表达水平与不利的治疗结果相关。因此，通过免疫效应细胞恢复/增强恶性细胞的NKG2D识别的新策略代表了在ALL中引发抗白血病免疫反应的有希望的免疫治疗方法。在拟议的项目中，我们的目标是开发新的抗体衍生物来特异性调节ALL中的NKG2D轴。我们的新药物的细胞毒性活性将在体外以及异种移植和同源ALL小鼠模型中进行测试。这些实验将为调节NKG2D轴是否代表治疗ALL的有效方法提供概念证明。

The natural killer group 2 member D (NKG2D) receptor / ligand axis plays a key role in the elimination of emerging tumor cells. The important roles for NKG2D in immunosurveillance of cancer have been supported in various animal models and in patients, where the risk of cancer development correlated with specific variants of the NKG2D encoding gene. NKG2D recognizes different protein ligands, which are expressed on the cell surface of virally infected cells and tumor cells and which act as danger signals. Recognition of these ligands triggers NK cell and T cell activation and results in elimination of ligand-expressing cells. During progression tumors escape this recognition through downregulation or shedding of NKG2D ligands. In AML, leukemia initiating cells have been demonstrated to lack NKG2D ligand expression thereby escaping immune recognition. In addition, in clinical studies, the expression of certain NKG2D ligands has been correlated with improved overall survival. Preliminary work based on RNA profiling suggests low NKG2D ligand expression levels in B cell leukemia and a correlation with an unfavorable treatment outcome. Therefore, novel strategies to restore / enhance NKG2D recognition of malignant cells by immune effector cells represent promising immunotherapeutic approaches to trigger antileukemia immune responses in ALL. In the proposed project we aim to develop novel antibody derivatives to specifically modulate the NKG2D axis in ALL. The cytotoxic activity of our novel agents will be tested in vitro as well as in xenograft and syngeneic mouse models of ALL. These experiments will provide proof of concept whether modulating the NKG2D axis represents a valid approach for the treatment of ALL.