Inducing NK cells to remember and fight cancer

诱导 NK 细胞记忆并对抗癌症

• 批准号: 8976605
• 负责人: Jeffrey S. Miller
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976605
• 关键词: Acute Myelocytic Leukemia; Adoptive Transfer; Affect; Allogenic; Antibody Affinity; Antigens; Basic Science; Biology; CD8B1 gene; Cancer Control; Cancer Relapse; Cell Differentiation process; Cell Survival; Cell Transplants; Cell physiology; Cells; Clinical; Clinical Research; Clonal Expansion; Cohort Studies; Complex; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA Methylation; Data; Development; Diamond; Disease; Disease remission; Education; Employee Strikes; Ensure; Epigenetic Process; Exhibits; FCGR3B gene; Frequencies; Genes; Goals; Grant; Health; Hematopoietic; Homing; Human; Immune; Immune system; Immunologist; Immunology; Immunotherapy; Individual; Infection; Inflammatory; Leukocytes; Life; Longevity; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory; Methods; MicroRNAs; Modeling; Molecular; Murid herpesvirus 1; Mus; Natural Killer Cells; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Process; Production; Property; Refractory; Role; SYK gene; Self Tolerance; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Translating; Transplant Recipients; Transplantation; Virus; Virus Diseases; base; cancer cell; cancer therapy; cell killing; chemotherapy; cohort; cytokine; deep sequencing; effective therapy; experience; fighting; genome-wide; hematopoietic cell transplantation; in vitro Assay; in vivo; interest; killings; leukemia; leukemia treatment; lymphoid enhancer-binding factor 1; mRNA Expression; notch protein; novel; programs; protein complex; receptor; reconstitution; relapse risk; response; seropositive; success; transcription factor; transcriptome; tumor; virology

 DESCRIPTION (provided by applicant): NK cells recognize virally infected and malignant cells and respond by direct target cell killing and the production of inflammatory cytokines. In humans, we have shown that adoptive transfer of NK cells can induce remission in patients with refractory acute myelogenous leukemia (AML) and that hematopoietic cell transplantation (HCT) can cure AML. Although clinical success is seen in both settings, NK cell survival and function are often suboptimal after transplant, resulting in cancer relapse. We have shown that AML patients who reactivate latent human cytomegalovirus (HCMV) post-HCT reconstitute more terminally differentiated NK cells with potent effector function relative to those who do not reactivate HCMV or are HCMV seronegative. Several clinical studies have also recently shown that HCMV reactivation early after HCT is associated with reduced relapse risk. The molecular basis for enhanced NK cell differentiation and function in response to HCMV is unknown. We have extensive preliminary data showing that, in healthy HCMV seropositive donors and in transplant recipients that experience HCMV reactivation, populations of NK cells lacking the proximal signaling molecules Fc¿R1g, SYK and EAT-2 expand. These novel NK cells have a genome wide epigenetic profile markedly similar to that of effector CD8+ T cells with a striking microRNA signature. They are present at stable frequencies over the course of at least one year, and they exhibit enhanced function in response to signaling through CD16. These cells appear to represent a human equivalent to adaptive or "memory" NK cells in mice that respond specifically to mouse cytomegalovirus (MCMV). Because of their functional and survival properties, there is considerable interest in being able to utilize them for immunotherapy. In this proposal, we aim to study the role of microRNAs in the differentiation of adaptive human NK cells upon HCMV reactivation in NK cells from our unique cohort of transplant patients using an unbiased, cutting-edge deep-sequencing approach. We will test the hypothesis that signaling through activating receptors is required for the expansion of adaptive NK cells and determine the role of pentameric HCMV protein complexes and high-affinity antibodies to these complexes in triggering expansion. We have preliminary data suggesting that the Notch/TCF-1 and Wnt signaling pathways are selectively induced in HCMV-induced adaptive NK cells, and we will study the role of both pathways in the development and differentiation of adaptive NK cells in depth using our well defined transplant cohorts and in vitro assays. We will also combine our recently developed xenogeneic model for adoptive human NK cell transfer with a new model for systemic HCMV infection in mice to study HCMV-induced adaptive NK cell survival, homing and function in vivo. Our team of leading basic and clinical NK cell biologists, HCMV experts and mouse immunologists are well positioned to perform these studies and translate them to therapies that can prime NK cells for potent function and prolonged survival for clinical use in the treatment of cancer.

 描述（由适用提供）：NK细胞识别几乎感染和恶性细胞，并通过直接靶细胞杀伤和炎症细胞因子的产生来做出反应。在人类中，我们已经表明，NK细胞的适应性转移可以诱导难治性急性粒细胞性白血病（AML）的患者缓解，并且造血细胞移植（HCT）可以治愈AML。尽管在这两种情况下都可以看到临床成功，但在移植后，NK细胞的存活和功能通常是次优的，导致癌症缓解。我们已经表明，与未重新激活HCMV或hCMV血清固定的人相对于那些不潜在的效应子功能，将潜在的人类巨细胞病毒（HCMV）重新激活的AML患者更终末分化的NK细胞。最近的一些临床研究还表明，HCT后早期的HCMV重新激活与降低的复发风险有关。增强NK细胞分化和响应HCMV功能的分子基础尚不清楚。我们有广泛的初步数据，表明，在健康的HCMV血清阳性供体中，在经历HCMV重新激活的移植受者中，缺乏近端信号分子的NK细胞种群FC¿R1G，SYK，SYK和EAT-2扩展。这些新型的NK细胞具有带有撞击microRNA特征的效应子CD8+ T细胞的基因组广泛的表观遗传谱。它们在至少一年的时间内以稳定的频率存在，并且通过CD16响应信号而暴露了增强功能。这些细胞似乎代表了针对小鼠的自适应或“记忆” NK细胞的人类，该细胞对小鼠巨细胞病毒（MCMV）有反应。由于它们的功能和生存特性，因此有很大的兴趣将其用于免疫疗法。在这个 提案，我们旨在研究MicroRNA在我们独特的移植患者中使用NK细胞中HCMV重新激活自适应人NK细胞在分化的作用，并使用一种无​​偏见的，尖端的，尖端的深层序列方法。我们将测试以下假设：通过激活受体的信号传导是自适应NK细胞的扩展所必需的，并确定五聚体HCMV蛋白复合物和对这些复合物在触发扩张中的高亲和力抗体的作用。我们有初步数据表明，Notch/TCF-1和Wnt信号通路在HCMV诱导的自适应NK细胞中被选择性诱导，我们将使用我们良好的定义的移植群和体外试验来研究途径在深度的自适应NK细胞在深度开发和区分深度的作用中的作用。我们还将将最近开发的用于自适应人NK细胞转移的异构模型与小鼠全身HCMV感染的新模型相结合，以研究HCMV诱导的自适应NK细胞存活，体内的归纳和功能。我们由领先的基本和临床NK细胞生物学家，HCMV专家和小鼠免疫学家组成的团队可以很好地进行这些研究，并将其转化为可以为NK细胞促进潜在功能并长期生存的疗法，以延长癌症治疗的临床使用。