NK effector mechanisms during NK-lymphoma interactions

描述(申请人提供)：众所周知，NK细胞在体外和体内都能杀死肿瘤细胞。另外，NK细胞表面的抑制性受体与MHC-I类分子的相互作用可以阻止NK细胞杀伤肿瘤细胞。我们的假设是，早期的NK细胞与肿瘤细胞的相互作用在确定NK细胞是促进抗肿瘤免疫还是阻止抗肿瘤免疫方面具有重要意义。这些相互作用在肿瘤生长早期很可能是重要的。此外，肿瘤细胞可能阻止NK细胞效应机制，从而阻止抗肿瘤免疫反应，促进肿瘤生存。数据表明，NK细胞是抵抗传染病和肿瘤的先天防御的一部分，NK细胞可以影响下游免疫。本研究的目的是探讨NK细胞能在多大程度上改变宿主对肿瘤的反应，以及NK细胞激活宿主巨噬细胞和杀伤T细胞对抗肿瘤细胞的机制。我们假设NK细胞的激活对于巨噬细胞的正确激活和产生长期杀伤肿瘤细胞的T细胞是重要的。我们的具体目标是：1)确定NK细胞抑制受体在多大程度上阻止宿主抗肿瘤反应的产生。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受体对抗肿瘤免疫的影响。2)确定NK细胞效应机制在不同巨噬细胞效应功能产生中的作用，即M1和M2巨噬细胞。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)确定在多大程度上能诱导NK细胞激活局部宿主抗肿瘤免疫反应。我们将尝试用肿瘤特异性抗体改变局部NK细胞的激活，并诱导炎性巨噬细胞。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反应。这些数据将对免疫治疗和肿瘤疫苗产生影响，并提出开发更有效的肿瘤免疫的方法。

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.