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被认为具有免疫抑制作用。许多特定的蛋白质已被确定，阻止充分激活浸润性免疫细胞。然而，目前尚不清楚肿瘤细胞如何在效应细胞存在的情况下启动一个允许生存的环境，而效应细胞已经进化到可以消灭它们。自然杀伤细胞（NK）是抗肿瘤反应中的一种效应细胞，它分泌炎症细胞因子并直接杀死转化的细胞。有重要的证据支持NK细胞在肿瘤发展的早期阶段参与消除转化细胞。在某个时刻，通过一种未知的机制，转化的细胞建立了一种方法来逃避这些细胞的识别，从而形成实体瘤。一旦肿瘤形成，细胞毒性免疫细胞消除肿瘤靶点的能力就会严重减弱，从而导致肿瘤生长，并进一步抑制局部和全身免疫。骨髓细胞的广泛募集被认为促进血管生成和转移，并阻止免疫细胞活化。利用细胞和分子生物学技术，我们将研究胶质母细胞瘤患者肿瘤细胞、它们募集的髓样细胞和NK细胞之间复杂的相互作用。我们假设骨髓细胞被招募来保护肿瘤细胞免受免疫识别，并可能作为癌症患者NK细胞的诱饵靶标。