NK cell-myeloid cell crosstalk in patients with cancer

项目摘要/摘要 长期以来，肿瘤微环境一直被认为是免疫抑制的。许多特定的蛋白质都有 已发现可防止充分激活渗入的免疫细胞。然而，目前还不知道是如何 肿瘤细胞启动了一种环境，允许在存在效应细胞的情况下存活，效应细胞已经进化到 消灭他们。在抗肿瘤反应中的一个这样的效应细胞是自然杀伤(NK)细胞，它分泌 炎症细胞因子，并直接杀死转化的细胞。有大量证据支持这一观点 NK细胞参与肿瘤发展早期转化细胞的清除。在… 某些点，通过一种未知机制，转化的细胞建立了一种方法，通过 这些细胞和实体瘤就会形成。一旦肿瘤被确定，细胞毒性免疫细胞的能力 消除肿瘤靶点严重减弱，允许肿瘤生长和进一步抑制局部和 系统免疫力。也有大量的髓系细胞被招募，据信可以促进血管生成和 转移，并防止免疫细胞激活。利用细胞和分子生物学技术，我们将 研究肿瘤细胞及其募集的髓系细胞与患者NK细胞之间的复杂相互作用 胶质母细胞瘤。我们假设招募髓系细胞是为了保护肿瘤细胞免受免疫 并可能成为癌症患者NK细胞的诱饵靶点。 我的研究计划详细说明了我在理解细胞和分子方面的近期和长期职业目标 控制肿瘤抑制局部和系统免疫的机制。我的近期目标是定义 肿瘤对髓系细胞表达NKG2D配体的影响以及这些髓系细胞如何反过来 调节NK细胞的功能。我们假设，通过诱导NKG2D配体在表面 髓系细胞、NK细胞的杀伤是从肿瘤细胞向大量髓系细胞的大量渗透。如果这些 NKG2D配体阳性的髓系细胞作为NK细胞的诱骗靶点，肿瘤将创造一个物理 屏障和促进存活、血管生成和转移免受细胞毒细胞的免疫保护 系统。我们已经证明NKG2D配体阳性的髓系细胞可以作为NK细胞的靶点，并且肿瘤- 衍生的可溶性蛋白诱导髓系细胞表达NKG2D配体。在这项提案中，我们将首先 评价NKG2D配体表达患者骨髓细胞对NK细胞功能的影响(目标1)。我们会 接下来确定肿瘤患者髓系细胞表达NKG2D配体是否可以作为一种 诊断或预后工具(目标2)。此外，我们还将分离和鉴定肿瘤来源的可溶性蛋白。 或诱导髓系细胞上NKG2D配体的蛋白质(目标3)。总而言之，这项研究工作将具有 重要的临床相关性，并将影响脑，肝细胞， 前列腺癌和乳腺癌。 成为助理教授后，我的长期目标包括形成跨学科的基础和临床 探索肿瘤如何影响患者的先天和获得性免疫反应的研究计划。vbl.使用 动物模型和患者样本，我的目标是发现肿瘤免疫抑制的机制并发展 对目前癌症患者免疫疗法的改进。我将完成这方面的指导阶段 在安德鲁·帕尔萨和刘易斯·拉尼尔博士的指导下提出建议，并期待着完成 这个项目的独立阶段，在另一所大学担任助理教授。

PROJECT SUMMARY/ABSTRACT The tumor microenvironment has long-been known to be immunosuppressive. Many specific proteins have been identified that prevent adequate activation of infiltrating immune cells. It is not known, however, how tumor cells initiate an environment that allows survival in the presence of effector cells that have evolved to eliminate them. One such effector cell in the antitumor response is the natural killer (NK) cell, which secretes inflammatory cytokines and directly kills transformed cells. There is significant evidence to support the involvement of NK cells in the elimination of transformed cells in the early stages of tumor development. At some point, through an unknown mechanism, transformed cells establish a method to escape recognition by these cells and a solid tumor develops. Once a tumor is established, the ability of cytotoxic immune cells to eliminate tumor targets is severely diminished, allowing tumor growth and further suppression of local and systemic immunity. There is also extensive recruitment of myeloid cells, believed to promote angiogenesis and metastasis, and prevent immune cell activation. Using cellular and molecular biological techniques, we will study the complex interactions between tumor cells, the myeloid cells that they recruit and NK cells in patients with glioblastoma. We hypothesize that myeloid cells are recruited to protect tumor cells from immune recognition, and may serve as decoy targets for NK cells in patients with cancer. My research plan details my immediate and long-term career goals in understanding the cellular and molecular mechanisms that govern tumor suppression of local and systemic immunity. My immediate goals are to define the impact of a tumor on NKG2D-ligand expression by myeloid cells and how these myeloid cells can, in turn, regulate the function of NK cells. We hypothesize that through induction of NKG2D ligands on the surface of myeloid cells, NK cell killing is redirected from tumor cells to the massive infiltration of myeloid cells. If these NKG2D ligand positive myeloid cells serve as decoy targets for NK cells, a tumor will have created a physical barrier and promote survival, angiogenesis and metastasis shielded from the cytotoxic cells of the immune system. We have shown that NKG2D ligand-positive myeloid cells can be targets for NK cells, and that tumor- derived soluble proteins induce NKG2D ligand expression on myeloid cells. In this proposal, we will first evaluate NK cell function in response to NKG2D ligand expressing myeloid cells from patients (Aim 1). We will next determine if NKG2D ligand expression by myeloid cells in patients with cancer can be used as a diagnostic or prognostic tool (Aim 2). Furthermore, we will isolate and identify the tumor-derived soluble protein or proteins that induce NKG2D ligands on myeloid cells (Aim 3). Altogether, this research effort will have important clinical relevance and will influence clinical management of patients with brain, hepatocellular, prostate, and breast cancer. My long-term goals after becoming an assistant professor include forming an interdisciplinary basic and clinical research program to explore how a tumor influences innate and adaptive immune responses in patients. Using animal models and patient samples, I aim to discover mechanisms of tumor immunosuppression and develop improvements to current immunotherapy for patients with cancer. I will complete the mentored phase of this proposal under the guidance of Drs. Andrew Parsa and Lewis Lanier and look forward to completing the independent phase of this project as an assistant professor at another university.