NK effector mechanisms during NK-lymphoma interactions

描述（由申请人提供）：众所周知，NK细胞可以在体外和体内杀死肿瘤细胞。还已知通过MHC I类分子和NK细胞上的抑制性受体的相互作用，可以防止NK细胞杀死肿瘤细胞。我们的假设是，早期NK细胞-肿瘤细胞相互作用在决定NK细胞是否促进抗肿瘤免疫或阻止抗肿瘤免疫方面是重要的。这些相互作用可能在肿瘤生长阶段的早期很重要。此外，肿瘤细胞可能会阻止NK细胞效应机制，从而阻止抗肿瘤免疫应答并促进肿瘤存活。数据表明，NK细胞是对抗感染性疾病和肿瘤的先天防御的一部分，NK细胞可以影响下游免疫。这项研究的目的是调查NK细胞可以改变宿主对肿瘤的反应的程度，以及NK细胞激活宿主巨噬细胞和溶细胞性T细胞对抗肿瘤细胞的机制。我们假设NK细胞活化对于巨噬细胞的适当活化和产生针对肿瘤细胞的长期溶细胞性T细胞是重要的。我们的具体目标是：1）确定NK细胞抑制性受体阻止宿主抗肿瘤应答产生的程度。我们将使用抗受体抗体和受体转基因小鼠来确定这些抑制性受体对抗肿瘤免疫的影响。2)确定NK细胞效应器机制在产生不同巨噬细胞效应器功能（即所谓的M1和M2巨噬细胞）中的作用。我们将利用转基因小鼠的体外和体内系统来测试关键的效应分子和途径。3)确定NK细胞可被诱导以激活局部宿主抗肿瘤免疫应答的程度。我们将尝试用肿瘤特异性抗体改变局部NK细胞活化并诱导炎症巨噬细胞。这些实验将涉及两种小鼠淋巴瘤模型：RMA和BW-Sp3肿瘤细胞。我们的目标是了解NK-肿瘤细胞相互作用如何促进或未能促进有效的抗肿瘤免疫应答。这些数据将对免疫治疗和肿瘤疫苗产生影响，并为开发更有效的肿瘤免疫提供建议。

DESCRIPTION (provided by applicant): It is well known that NK cells can kill tumor cells in vitro and in vivo. It is also known that NK cells can be prevented from killing tumor cells by the interaction of MHC class I molecules and inhibitory receptors on NK cells. Our hypothesis is that the early NK cell-tumor cell interaction is important in determining whether NK cells promote anti-tumor immunity or prevent anti-tumor immunity. These interactions are likely to be important early in the growth phase of a tumor. Furthermore, it may be possible that tumor cells can prevent NK cell effector mechanisms and thus prevent anti-tumor immune responses and promote tumor survival. Data suggest that NK cells are a part of the innate defense against infectious diseases and tumors, and NK cells can influence downstream immunity. The aim of this research proposal is to investigate the extent to which NK cells can alter host responses to tumors and the mechanisms that NK cells employ to activate host macrophages and cytolytic T cells against tumor cells. We hypothesize that NK cell activation is important for the proper activation of macrophages and the production of long-term cytolytic T cells against tumor cells. Our specific aims are: 1) to determine the extent to which NK cell inhibitory receptors prevent the generation of a host anti-tumor response. We will use anti-receptor antibodies and receptor transgenic mice to determine the influence of these inhibitory receptors on anti-tumor immunity. 2) To determine the role of NK cell effector mechanisms in the generation of different macrophage effector functions, so called M1 and M2 macrophages. We will utilize in vitro and in vivo systems with genetically altered mice to test key effector molecules and pathways. 3) To determine the extent to which NK cells can be induced to activate local host anti-tumor immune responses. We will attempt to alter local NK cell activation with tumor specific antibodies and induce inflammatory macrophages. These experiments will involve two murine lymphoma models: RMA andBW-Sp3 tumor cells. We aim to understand how NK-tumor cell interactions promote or fail to promote effective anti-tumor immune responses. These data will have implications for immunotherapy and tumor vaccines and suggest ways to develop more potent tumor immunity.