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Mechanisms underlying cytokine-induced memory-like natural killer cell differentiation and maintenance.

细胞因子诱导的记忆样自然杀伤细胞分化和维持的机制。

基本信息

批准号：
8983154
负责人：
Melissa Berrien Elliott
金额：
$ 5.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983154
关键词：
Acute Myelocytic Leukemia Adoptive Immunotherapy Adoptive Transfer Allogenic B-Lymphocytes Blood specimen Boxing Candidate Disease Gene Cell Differentiation process Cell Maintenance Cell division Cell physiology Cells Cellular biology Clinical Clinical Trials Correlative Study Cytokine Activation DNA DNA Methylation Data Data Set Disease Disease remission Epigenetic Process Exhibits Flow Cytometry Gene Expression Generations Granzyme Haptens Hematologic Neoplasms Histones Human IL2RA gene Immune Immunotherapy In Vitro Infusion procedures Interferon Type II Interleukin-12 Interleukin-15 Interleukin-18 Investigation Laboratories Laboratory Study Lead Lymphoid Cell Maintenance Malignant Neoplasms Memory Messenger RNA Methylation Minority Molecular Mus Natural Killer Cells Patients Phase I Clinical Trials Phenotype Prevalence Primary Neoplasm Property Refractory Regulation Relapse Reporting Role Sampling Scientific Advances and Accomplishments T-Lymphocyte Therapeutic Time Transcriptional Regulation Tumor Immunity Up-Regulation Virus Diseases Work Xenograft Model base cytokine daughter cell differential expression epigenetic regulation gain of function gene function histone modification human study improved in vitro activity in vivo knock-down lentivirally transduced leukemia loss of function novel strategies outcome forecast phase 1 study preclinical study programs promoter public health relevance response small hairpin RNA transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a common hematologic malignancy with an estimated prevalence of 3.8 cases per 100,000. Patients with relapsed/refractory (rel/ref) AML have poor prognosis and new, well tolerated therapeutic options are needed. Recently, paradigm changing studies of murine natural killer (NK) cells have identified that these innate immune cells have memory-like properties. Our lab has confirmed cytokine-induced memory-like (CIML) NK cells in humans. Further, pre-clinical studies have demonstrated that human CIML NK cells have superior anti-leukemia activity in vitro and in xenograft models. We will utilize samples from the first- in-human study of CIML NK cells in AML patients to perform correlative studies evaluating CIML NK cell expansion, survival, activation, and functions in patients. Samples collected from patients at various time points before and after allogeneic donor NK cell infusion and the indicated parameters evaluated by flow cytometry. We expect that human CIML NK cells will exhibit enhance expansion in vivo as well as enhance effector function against primary tumors ex vivo. Our proposed work will concurrently examine human CIML NK cells in the context of adoptive immunotherapy for the treatment of AML, as well as the underlying mechanisms that contribute to the differentiation, maintenance, and enhanced effector function upon secondary activation. Understanding these mechanisms will expand the clinical potential of CIML NK cells. The T-box transcription factor Eomes has been shown to be involved in NK cell effector function and preliminary data from our lab suggest it is upregulated in CIML NK cells compared to controls. Here we will utilize and loss- and gain-of-function analyses to determine if Eomes is necessary and sufficient, respectively, to promote CIML NK cell differentiation and effector function. This will be achieved by lentivirally transducing human CIML NK cells, resulting in the expression of Eomes (gain-of function) or Eomes shRNA (knock-down). We expect that if Eomes is important for CIML NK cell biology, knock-down of its expression will abrogate CIML NK cell differentiation or function. Likewise, if Eomes is sufficient for CIML induction, its forced expression will lead to the enhanced function of NK cells regardless of cytokine pre-activation. Since CIML NK cell function is passed on to daughter cells, we hypothesize that epigenetic mechanisms contribute to their enhanced functional program. We will examine the histone modifications and DNA methylation status of candidate genes, comparing naive, pre-activated, and CIML NK cells. We will focus on candidate genes that are functionally important and differentially expressed in CIML versus control NK cells. We expect that the enhanced responsiveness observed by CIML NK cells will correlate with candidate genes that display active histone marks and decreased DNA promoter methylation in CIML NK cells compared to controls.