NK cell-myeloid cell crosstalk in patients with cancer

癌症患者中的 NK 细胞-骨髓细胞串扰

• 批准号: 8721722
• 负责人: Courtney Crane
• 金额: $ 23.83万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-19 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721722
• 关键词: Activated Natural Killer Cell; Active Immunotherapy; Animal Model; Antitumor Response; Autologous; Basic Science; Biological; Biological Assay; Biological Markers; Blocking Antibodies; Blood Circulation; Brain Neoplasms; Breast Carcinoma; CD8B1 gene; Cancer Patient; Cell physiology; Cells; Chromium; Clinical; Clinical Management; Clinical Research; Complex; Cytolysis; Data; Development; Diagnostic; Diagnostic Neoplasm Staging; Effector Cell; Environment; Flow Cytometry; Glioblastoma; Goals; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infiltration; Inflammatory; Inflammatory Response; Interferon Type II; Label; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Measures; Mediating; Mentors; Methods; Molecular; Monitor; Myeloid Cells; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Phase; Primary carcinoma of the liver cells; Production; Prostate carcinoma; Proteins; Recruitment Activity; Recurrence; Relative (related person); Research; Risk; Sampling; Small Interfering RNA; Solid Neoplasm; Steroids; Surface; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Tumor Burden; Tumor Escape; Tumor Suppression; Tumor stage; Tumor-Derived; Tumor-Secreted Protein; Universities; Work; angiogenesis; base; cancer immunotherapy; cancer type; career; cell killing; cell transformation; chemotherapy; clinically relevant; cytokine; cytotoxic; improved; insight; killings; malignant breast neoplasm; minimally invasive; mouse model; neoplastic cell; novel; overexpression; patient population; peripheral blood; prevent; professor; prognostic; programs; public health relevance; receptor; research study; response; tool; tumor; tumor growth; tumor microenvironment

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.

项目摘要/摘要 肿瘤微环境已知已知是免疫抑制的。许多特定蛋白质具有 已确定可以防止充分激活浸润的免疫细胞。但是，尚不清楚 肿瘤细胞启动一个环境，该环境允许在效应细胞存在的情况下生存为 消除它们。抗肿瘤反应中的一种这样的效应细胞是天然杀手（NK）细胞，该细胞分泌 炎性细胞因子并直接杀死转化的细胞。有大量证据支持 在肿瘤发育的早期阶段，NK细胞参与消除转化的细胞。在 通过未知的机制，有些点转化的细胞建立了一种逃避识别的方法 这些细胞和实体瘤形成。一旦建立肿瘤，细胞毒性免疫细胞的能力 消除肿瘤靶标会严重减少，从而使肿瘤生长并进一步抑制局部和 系统性免疫。还广泛募集髓样细胞，据信促进血管生成和 转移，并防止免疫细胞活化。使用细胞和分子生物学技术，我们将 研究患者募集和NK细胞的肿瘤细胞之间的复杂相互作用 与胶质母细胞瘤。我们假设募集髓样细胞以保护肿瘤细胞免疫 识别，可以作为癌症患者NK细胞的诱饵靶标。 我的研究计划详细介绍了我了解细胞和分子的直接和长期职业目标 控制局部和全身免疫的肿瘤抑制的机制。我的直接目标是定义 肿瘤对髓样细胞的NKG2D-配体表达的影响，以及这些髓样细胞如何依次可以 调节NK细胞的功能。我们假设通过在表面上诱导NKG2D配体 髓样细胞，NK细胞杀伤从肿瘤细胞重定向到髓样细胞的大量浸润。如果这些 NKG2D配体阳性髓样细胞是NK细胞的诱饵靶标，肿瘤将产生物理 障碍和促进从免疫细胞的细胞毒性细胞掩盖的生存，血管生成和转移 系统。我们已经表明，NKG2D配体阳性髓样细胞可以是NK细胞的靶标，并且肿瘤 - 衍生的可溶性蛋白在髓样细胞上诱导NKG2D配体的表达。在此提案中，我们将首先 评估NK细胞功能，响应于表达患者的髓样细胞的NKG2D配体（AIM 1）。我们将 接下来，确定髓样细胞在癌症患者中的NKG2D配体表达是否可以用作 诊断或预后工具（AIM 2）。此外，我们将隔离并鉴定肿瘤衍生的可溶性蛋白 或在髓样细胞上诱导NKG2D配体的蛋白质（AIM 3）。总之，这项研究工作将 重要的临床相关性，并将影响大脑，肝细胞癌患者的临床管理 前列腺和乳腺癌。 成为助理教授后的长期目标包括成立跨学科基础和临床 探索肿瘤如何影响患者先天和适应性免疫反应的研究计划。使用 动物模型和患者样品，我的目的是发现肿瘤免疫抑制的机制并发展 改善癌症患者的当前免疫疗法。我将完成这一指导阶段 在Drs的指导下的提案。安德鲁·帕萨（Andrew Parsa）和刘易斯·拉尼尔（Lewis Lanier），期待完成 该项目的独立阶段是另一所大学的助理教授。