Mechanism of CD8 regulation of natural killer cell biology

CD8调节自然杀伤细胞生物学的机制

• 批准号: 10356062
• 负责人: Celia Claire Cubitt
• 金额: $ 3.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356062
• 关键词: ATAC-seq; Acute Myelocytic Leukemia; Adoptive Cell Transfers; Antitumor Response; Attenuated; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; CD8 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chromatin; Clinical; Clinical Trials; Cytokine Receptors; Data; Defect; Disease remission; Epigenetic Process; Equilibrium; Exhibits; Future; Genes; Glycoproteins; Goals; Hematologic Neoplasms; Human; Immune; Immunologic Surveillance; In Vitro; Infection; Interleukin-12; Interleukin-15; Interleukin-18; Length; Leukemic Cell; Lymphoid Cell; MHC Class I Genes; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Memory; Metabolic; Metabolic Pathway; Modeling; Molecular; Mus; NK Cell Activation; NK cell therapy; Natural Killer Cells; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Phenotype; Population; Production; Receptor Signaling; Refractory; Regulation; Relapse; Role; Safety; Signal Transduction; System; T-Cell Receptor; T-Lymphocyte; Treatment Failure; Treatment outcome; Viral; Work; anti-tumor immune response; base; cell transformation; cell type; chemotherapy; curative treatments; cytokine; cytotoxic; cytotoxicity; first-in-human; hematopoietic cell transplantation; improved; in vivo; in vivo Model; insight; knock-down; loss of function; phase 1 study; receptor; receptor expression; recruit; response; telomere; therapy design; treatment response; tumor

Project Summary Hematologic malignancies such as acute myeloid leukemia (AML) remain clinically challenging and refractory to traditional chemotherapy approaches. For many patients, hematopoietic cell transplant (HCT) is the only curative treatment, whereby part of the efficacy is driven by donor natural killer (NK) cells that target the recipient’s leukemic cells. Natural killer cell adoptive therapy for AML patients represent a promising approach for improving patient outcomes. Work done in the Fehniger lab has defined a strategy to induce a memory-like (ML) phenotype of isolated NK cells using a stimulation with IL-12, IL-15, and IL-18 that demonstrates enhanced proliferation, cytotoxicity, and persistence both in vitro and in vivo. A phase 1 study using ML NK cells in relapsed/refractory AML patients showed approximately 50% of patients achieving a complete remission, although the mechanisms driving treatment failure are not clearly understood. Multidimensional immune correlative analysis of donor NK cells identified a negative association between CD8 expression on NK cells and treatment response. However, the role of CD8 on human conventional and ML NK cells remains unknown. The proposed project aims to understand the mechanism by which CD8 expression impacts conventional and ML NK cell biology, and has broad implications for understanding NK cell responses in cancer, infection, and autoimmunity. Preliminary data demonstrate that CD8+ NK cells have a diminished proliferative capacity compared to CD8- NK cells both in vitro and in vivo. We hypothesize that CD8 expression on donor NK cells negatively impacts overall NK cell responses against AML. Aim 1 of this proposal focuses on determining the mechanisms by which CD8+ conventional and ML NK cells have compromised proliferation, and the subsequent impact on tumor control in vivo. Specifically, the contributions of telomere length, chromatin accessibility, and metabolic differences will be investigated. Aim 2 focuses on defining the function of the CD8 molecule itself through highly efficient CRISPR-Cas9 based knockdown, and the subsequent impact on conventional and ML NK cell cytotoxicity, signaling, and survival. Together, these results will further inform future NK cell therapy designs and enhance our understanding of CD8 and its contributions to fundamental aspects of NK cell biology.

项目摘要 血液恶性肿瘤如急性髓性白血病（AML）仍然具有临床挑战性， 对传统化疗方法无效。对于许多患者来说，造血细胞移植（HCT）是最好的选择。 只有治愈性治疗，其中部分疗效是由靶向患者的供体自然杀伤（NK）细胞驱动的。 接受者的白血病细胞。AML患者的自然杀伤细胞过继治疗代表了一种有前途的方法 用于改善患者的结果。在Fehniger实验室完成的工作已经定义了一种策略， (ML)使用IL-12、IL-15和IL-18刺激的分离的NK细胞的表型， 增殖、细胞毒性和体内体外持久性。一项使用ML NK细胞的I期研究， 复发性/难治性AML患者显示约50%的患者达到完全缓解， 尽管导致治疗失败的机制还不清楚。 供体NK细胞的多维免疫相关分析确定了 NK细胞上的CD 8表达和治疗反应。然而，CD 8在人类常规和ML中的作用 NK细胞仍然未知。 拟议的项目旨在了解CD 8表达影响常规免疫的机制。 和ML NK细胞生物学，并对理解癌症，感染， 和自身免疫初步数据表明，CD 8 + NK细胞具有降低的增殖能力， 与体内和体外的CD 8- NK细胞相比。我们假设供体NK细胞上的CD 8表达 负面影响针对AML的总体NK细胞应答。本提案的目标1侧重于确定 CD 8+常规和ML NK细胞损害增殖的机制，以及随后的 对体内肿瘤控制影响。具体来说，端粒长度，染色质可及性， 将研究代谢差异。目标2：定义CD 8分子本身的功能 通过高效的基于CRISPR-Cas9的敲除，以及随后对传统和ML的影响， NK细胞的细胞毒性、信号传导和存活。总之，这些结果将进一步为未来的NK细胞治疗提供信息 设计和增强我们对CD 8及其对NK细胞生物学基本方面的贡献的理解。