The role of NKG2D ligands in myeloid cell-NK cell crosstalk in cancer patients

NKG2D 配体在癌症患者骨髓细胞-NK 细胞串扰中的作用

• 批准号: 7950217
• 负责人: Courtney Crane
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950217
• 关键词: Activated Natural Killer Cell; Active Immunotherapy; Animal Model; Antitumor Response; Autologous; Biological; Biological Assay; Biological Markers; Blocking Antibodies; Blood Circulation; Brain; Brain Neoplasms; Breast; 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; 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; Proteins; Recruitment Activity; Recurrence; Relative (related person); Research; Risk; Role; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The focus of my research has been aimed at defining the impact of tumor burden on the function of cytotoxic immune cells in patients with glioblastoma. This work will have broad implications in the development of novel patient therapies that capitalize on improvements of Natural Killer and CD8+ T cell function. The work proposed in this application will identify a potential mechanism of immune evasion by glioblastoma. This project may also be widely applicable to monitoring at risk patient populations using a novel biomarker for cancer. Finally, this project will identify a novel soluble protein target for immune therapy in glioblastoma and possibly in other cancer patients. By gaining a better understanding of how tumors can systemically and locally impact cells of the immune system, and mechanisms for tumor escape of immune recognition, we hope to improve preventative and therapeutic approaches in the battle against cancer.

描述（由申请人提供）：肿瘤微环境长期以来已知是免疫抑制的。已经确定了许多特定的蛋白质，以防止充分激活浸润的免疫细胞。然而，尚不清楚肿瘤细胞如何启动一个环境，该环境允许在有效细胞存在以消除它们的情况下生存。抗肿瘤反应中的效应细胞之一是天然杀伤（NK）细胞，该细胞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NK细胞在肿瘤发育的早期消除转化细胞中的参与。在某个时候，通过未知的机制，转化的细胞建立了一种逃避这些细胞识别和实体瘤识别的方法。一旦建立了肿瘤，细胞毒性免疫细胞消除肿瘤靶标的能力将大大减少，从而允许肿瘤生长并进一步抑制局部和全身免疫。还广泛募集髓样细胞，据信促进血管生成和转移，并防止免疫细胞激活。使用细胞和分子生物学技术，我们将研究胶质母细胞瘤患者中肿瘤细胞，骨髓细胞和NK细胞之间的复杂相互作用。我们假设募集髓样细胞以保护肿瘤细胞免疫识别，并可以作为癌症患者NK细胞的诱饵靶标。 我的研究计划详细介绍了我的直接和长期职业目标，以了解控制局部和全身免疫抑制肿瘤的细胞和分子机制。我的直接目标是定义肿瘤对髓样细胞NKG2D-grigand表达的影响，以及这些髓样细胞如何依次调节NK细胞的功能。我们假设，通过在髓样细胞表面诱导NKG2D配体，NK细胞杀死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，则肿瘤将产生物理屏障并促进与免疫系统细胞毒性细胞相比的生存，血管生成和转移。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，以响应于表达患者的髓样细胞的NKG2D配体（AIM 1）。接下来，我们将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，我们将分离并鉴定肿瘤衍生的可溶性蛋白或蛋白质，这些蛋白质或蛋白质在髓样细胞上诱导NKG2D配体（AIM 3）。总的来说，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，前列腺和乳腺癌患者的临床管理。 我成为助理教授后的长期目标包括成立跨学科基础和临床研究计划，以探索肿瘤如何影响患者的先天和适应性免疫反应。我旨在使用动物模型和患者样品，以发现肿瘤免疫抑制的机制，并为癌症患者的当前免疫疗法改善。我将在DRS的指导下完成该提案的指导阶段。安德鲁·帕尔萨（Andrew Parsa）和刘易斯·拉尼尔（Lewis Lanier），期待完成该项目的独立阶段，成为另一所大学的助理教授。 公共卫生相关性：我的研究的重点旨在定义肿瘤负担对胶质母细胞瘤患者细胞毒性免疫细胞功能的影响。这项工作将对新型患者疗法的发展具有广泛的影响，这些疗法利用了自然杀手和CD8+ T细胞功能的改善。本应用中提出的工作将确定胶质母细胞瘤免疫逃避的潜在机制。该项目也可能广泛适用于使用新型癌症生物标志物监测风险的患者人群。最后，该项目将确定一种新型的可溶性蛋白质靶标，用于胶质母细胞瘤以及其他癌症患者的免疫治疗。通过更好地了解肿瘤如何系统地和局部影响免疫系统的细胞以及免疫识别的肿瘤逃生机制，我们希望在抗癌斗争中改善预防和治疗方法。