Elucidation of Human Natural Killer Cell Development

人类自然杀伤细胞发育的阐明

基本信息

批准号：
10587566
负责人：
AHARON G FREUD
金额：
$ 57.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587566
关键词：
Acute Myelocytic Leukemia Address Award Biological Assay Blood Bone Marrow CD34 gene Cancer Etiology Cancer Model Cancer Patient Cell Differentiation process Cell Lineage Cell Separation Cell physiology Cells Cessation of life Clinical Coculture Techniques Complement Data Development Developmental Cell Biology Developmental Process Effector Cell Endometrial Endometrial Carcinoma Fetal Development Fostering Funding Future Genetic Transcription Goals Growth Head and Neck Squamous Cell Carcinoma Hematopoietic stem cells Human Immune Immune Targeting Immune system Immunity Immunologic Surveillance Immunosuppression Immunotherapy In Vitro Innate Immune System Institution Invaded Knowledge Light Lymphoid Cell Lymphoid Tissue Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Measurement Mediating Methodology Methods Modeling Molecular Mus Natural Immunity Natural Killer Cells Outcome Pathway interactions Peripheral Phenotype Physiological Physiological Processes Play Pregnancy Process Production Property Public Health Publishing Regulation Reporting Role Scientist Series Shapes Signal Transduction System T-Lymphocyte Testing Therapeutic Tissues Tonsil Tumor Cell Invasion Tumor Immunity Tumor Promotion Tumor-Derived United States Uterus Woman Work angiogenesis cancer cell cancer immunotherapy clinically relevant cytotoxic design developmental plasticity experimental study fibrosarcoma human tissue improved in vivo lymph nodes melanoma mouse model neoplastic cell novel permissiveness precursor cell prevent prognostic programs stem therapeutic target therapy design tumor tumor growth tumorigenic

项目摘要

PROJECT SUMMARY This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development in the healthy state and in the setting of uterine endometrial carcinoma (EC). NK cells are cytotoxic “group 1” innate lymphoid cells (ILCs) that play myriad roles in immunity and are vital to controlling malignant transformation. NK cells undergo terminal differentiation and maturation in various tissues throughout the body, leading to a broad spectrum of NK cell phenotypes and functions. So-called conventional NK cells (cNK) that arise in secondary lymphoid tissues and predominate in the blood have established roles in complementing T cell-mediated immune surveillance. In contrast, specialized tissue-resident NK cells (trNK) and their close cousins, ILC1s, develop in various tissues and are retained there to carry out distinct functions. In the uterus, trNK cells and ILC1s are physiologically designed to support and promote pregnancy by promoting placental tissue invasion, immune suppression, and angiogenesis. We hypothesize that in the setting of EC the normal processes of uterine trNK cell and ILC1 development and function are co-opted by the tumor cells to promote their growth and invasion. Our goals in this proposal are to gain a comprehensive understanding of the cellular and molecular components that regulate human NK cell development in healthy tissues and to determine how these processes are impacted in the setting of EC. Our two specific aims are: 1) To define NK cell and ILC1 developmental pathways in human tissues; and 2) To determine how NK cell development and function are shaped by human EC. In particular, in Aim 1 we will test the hypothesis that all NK cells and ILC1s stem from a common group 1 ILC precursor cell, which we have recently identified in human lymphoid tissues. We propose a series of experiments to test our hypothesis and to determine the molecular regulation of the NK cell versus ILC1 developmental axis stemming from the novel precursor cell. Further, we will elucidate the developmental pathways of NK cells and ILC1s in the healthy human uterus, testing the hypothesis that uterine NK cells and ILC1s also stem from a similar group 1 ILC precursor cell but ultimately terminally differentiate through pathways distinct from those in lymphoid tissues. In Aim 2 we will test the hypothesis that NK cell development from the common group 1 ILC precursor is skewed towards the production of ILC1s and poorly cytotoxic uterine trNK cells that are permissive if not promoting of tumor growth. Through our proposed studies we will determine how NK cell development, functional diversity, and plasticity are shaped by EC. The clinical importance of these studies lies in the fact that EC is the most common gynecologic malignancy in the United States and is the sixth leading cause of cancer death in women. Further, we predict that the knowledge gained from our studies will improve our fundamental understand of human NK cell developmental biology and ultimately the design of future immune-based cancer therapies for EC and potentially other forms of cancer in which innate immunity is impacted.

项目概要该提案的重点是阐明调节人类自然杀伤 (NK) 细胞发育的过程在健康状态和子宫内膜癌 (EC) 情况下 NK 细胞具有细胞毒性“1 组”。先天性淋巴细胞 (ILC) 在免疫中发挥着多种作用，对于控制恶性细胞至关重要 NK细胞在整个过程中的各种组织中经历终末分化和成熟。产生广泛的 NK 细胞表型和功能，即所谓的传统 NK 细胞 (cNK)。产生于次级淋巴组织并在血液中占主导地位，已在以下方面发挥作用：相比之下，专门的组织驻留 NK 细胞 (trNK) 可以补充 T 细胞介导的免疫监视。它们的近亲 ILC1 在各种组织中发育并保留在那里以执行不同的功能。在子宫中，trNK 细胞和 ILC1 在生理上被设计为通过以下方式支持和促进妊娠：促进胎盘组织侵袭、免疫抑制和血管生成。 EC 的设置子宫 trNK 细胞和 ILC1 发育和功能的正常过程是由我们的目标是获得全面的肿瘤细胞生长和侵袭能力。了解调节人类 NK 细胞健康发育的细胞和分子成分组织并确定这些过程在 EC 环境中如何受到影响，我们的两个具体目标是：1) 定义 NK 细胞和 ILC1 在人体组织中的发育途径；2) 确定 NK 细胞如何发育；发育和功能由人类 EC 决定。特别是，在目标 1 中，我们将检验所有假设。 NK 细胞和 ILC1 源自共同的第 1 组 ILC 前体细胞，我们最近在我们提出了一系列实验来检验我们的假设并确定 NK 细胞与源于新型前体细胞的 ILC1 发育轴的分子调节。此外，我们将阐明健康人类子宫中 NK 细胞和 ILC1 的发育途径，检验子宫 NK 细胞和 ILC1 也源自类似的第 1 组 ILC 前体细胞的假设，但在目标 2 中，我们将最终区分出与淋巴组织中不同的途径。检验以下假设：从常见的第 1 组 ILC 前体开始的 NK 细胞发育偏向于 ILC1 和低细胞毒性子宫 trNK 细胞的产生，即使不促进肿瘤，也是允许的通过我们提出的研究，我们将确定 NK 细胞的发育、功能多样性和生长。可塑性由 EC 决定，这些研究的临床重要性在于 EC 是最重要的。是美国常见的妇科恶性肿瘤，是癌症死亡的第六大原因此外，我们预测从我们的研究中获得的知识将改善我们的基础。了解人类 NK 细胞发育生物学并最终设计未来基于免疫的癌症针对先天免疫受到影响的 EC 和潜在其他形式的癌症的治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma.

高细胞毒性自然杀伤细胞与皮肤 T 细胞淋巴瘤患者的不良预后相关。

DOI：
发表时间：
2018
期刊：
影响因子：
7.5
作者：
Mundy;Denlinger, Nathan;McLaughlin, Eric;Chakravarti, Nitin;Hwang, Susan;Chen, Li;Mao, Hsiaoyin Charlene;Kline, David;Youssef, Youssef;Kohnken, Rebecca;Lee, Dean Anthony;Lozanski, Gerard;Freud, Aharon G;Porcu, Pierluigi;Willia
通讯作者：
Willia

Abundant binary promoter switches in lineage-determining transcription factors indicate a digital component of cell fate determination.

谱系决定转录因子中丰富的二元启动子开关表明细胞命运决定的数字成分。

DOI：
发表时间：
2023-11-28
期刊：
影响因子：
8.8
作者：
Li, Hongchuan;Rahman, Md Ahasanur;Ruesch, Michael;Eisele, Caprice D;Anderson, Erik M;Wright, Paul W;Cao, Jennie;Ratnayake, Shashikala;Chen, Qingrong;Yan, Chunhua;Meerzaman, Daoud;Abraham, Roshini S;Freud, Aharon G;Anderson, Stephen K
通讯作者：
Anderson, Stephen K

Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells.

先天淋巴细胞时代的人类自然杀伤细胞发育建模。