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Mechanism of CD8 regulation of natural killer cell biology

CD8调节自然杀伤细胞生物学的机制

基本信息

批准号：
10557789
负责人：
Celia Claire Cubitt
金额：
$ 3.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10557789
关键词：
ATAC-seq Acute Myelocytic Leukemia Adoptive Cell Transfers Antitumor Response 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 Dimensions Disease remission Epigenetic Process Equilibrium Exhibits Future Genes Goals Hematologic Neoplasms Human IL18 gene Immune Immunologic Surveillance In Vitro Infection Inflammatory Interleukin-12 Interleukin-15 Length Leukemic Cell Lymphoid Cell MHC Class I Genes Malignant - descriptor Malignant Neoplasms Measures Mediating Membrane Glycoproteins 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 Prediction of Response to Therapy Production Proliferating 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 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

项目摘要

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.

项目总结