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.

项目总结/摘要 肿瘤微环境长期以来被认为是免疫抑制的。许多特定的蛋白质 被鉴定为阻止浸润免疫细胞的充分激活。然而，目前尚不清楚， 肿瘤细胞启动了一个环境，该环境允许在效应细胞存在的情况下存活， 消灭他们。抗肿瘤反应中的一种这样的效应细胞是自然杀伤（NK）细胞，其分泌 炎性细胞因子并直接杀死转化的细胞。有大量证据表明， NK细胞参与肿瘤发展早期转化细胞的消除。在 在某些情况下，通过未知的机制，转化细胞建立了一种逃避识别的方法， 这些细胞和实体瘤的发展。一旦肿瘤建立，细胞毒性免疫细胞的能力， 消除肿瘤靶点的能力严重减弱，使肿瘤生长和局部和局部的进一步抑制成为可能。 全身免疫还存在广泛的骨髓细胞募集，其被认为促进血管生成， 转移，并防止免疫细胞活化。利用细胞和分子生物学技术， 研究肿瘤细胞、它们募集的髓样细胞和患者体内NK细胞之间复杂的相互作用， 胶质母细胞瘤我们假设骨髓细胞被募集来保护肿瘤细胞免受免疫抑制， 这可能是一种新的识别方法，并且可以作为癌症患者NK细胞的诱饵靶标。 我的研究计划详细说明了我在理解细胞和分子生物学方面的近期和长期职业目标。 控制肿瘤抑制局部和全身免疫的机制。我的近期目标是 肿瘤对髓系细胞NKG 2D配体表达的影响，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，通过在细胞表面诱导NKG 2D配体， 当NK细胞杀伤骨髓细胞时，NK细胞杀伤从肿瘤细胞重定向到骨髓细胞的大量浸润。如果这些 NKG 2D配体阳性髓样细胞作为NK细胞的诱饵靶点，肿瘤将产生一个物理靶点。 屏障和促进生存，血管生成和转移屏蔽从免疫细胞毒性细胞 系统我们已经证明，NKG 2D配体阳性的髓样细胞可以成为NK细胞的靶细胞，并且肿瘤- 衍生的可溶性蛋白诱导骨髓细胞上NKG 2D配体表达。在这份提案中，我们将首先 评价NK细胞对来自患者的表达NKG 2D配体的髓样细胞的应答功能（目的1）。我们将 下一步确定癌症患者骨髓细胞的NKG 2D配体表达是否可以用作 诊断或预后工具（目标2）。此外，我们将分离和鉴定肿瘤源性可溶性蛋白 或诱导骨髓细胞上的NKG 2D配体的蛋白质（Aim 3）。总之，这项研究工作将有 重要的临床相关性，并将影响脑，肝细胞， 前列腺癌和乳腺癌。 我成为助理教授后的长期目标包括形成一个跨学科的基础和临床 研究计划，探索肿瘤如何影响患者的先天性和适应性免疫反应。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， 改善目前癌症患者的免疫疗法。我会完成这一指导阶段 在安德鲁·帕萨博士和刘易斯·拉尼尔博士的指导下， 作为另一所大学的助理教授，独立完成该项目。