Roles of CD2 and 2B4 in invariant natural killer T (iNKT) cell functions.

CD2 和 2B4 在不变自然杀伤 T (iNKT) 细胞功能中的作用。

基本信息

批准号：
9324159
负责人：
Rupali Das
金额：
$ 17.65万
依托单位：
MICHIGAN STATE 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：
2015-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324159
关键词：
Advisory Committees Affect Affinity Agonist Antibodies Antigens B-Lymphocytes Binding CD58 Antigens Cancer Patient Cell Communication Cell Surface Receptors Cell Therapy Cell physiology Cells Cellular biology Clinical Co-Immunoprecipitations Collaborations Committee Members Confocal Microscopy Cytolysis Cytoplasmic Tail Cytotoxic T-Lymphocytes Dendritic Cells Development Exhibits Flow Cytometry Galactosylceramides Gene Silencing Genotype Goals Hematopoietic Neoplasms Histologic Human Image Immune Immune response Immunity Immunoglobulins In Vitro Injectable Investigation Jordan Kinetics Knowledge Ligands Lipids Luciferases Lymphocyte Malignant - descriptor Malignant Neoplasms Mediating Mentors Modeling Movement Mus Natural Killer Cells Oranges Pediatric Hospitals Pennsylvania Philadelphia Phosphorylation Play Production Recruitment Activity Resources Role Signal Transduction Signaling Protein Site T-Cell Receptor T-Lymphocyte Testing Therapeutic Training Programs Universities Up-Regulation antitumor effect base cancer immunotherapy cancer therapy career development cell killing cell type cytokine cytotoxic cytotoxicity defined contribution human disease immune activation immunological synapse immunological synapse formation improved in vivo insight killings mutant neoplastic cell novel pathogen public health relevance receptor reconstitution response tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that participate in host immunity to cancer. Despite the recognition that iNKT cells promote anti-tumor immune responses, many questions remain regarding how these cells recognize and respond to tumor cells. This lack of information impedes the development of novel and potentially more effective iNKT cell-based immunotherapies for cancer. My studies reveal that primary murine and human iNKT cells exhibit robust T cell receptor (TCR)-induced cytolytic activity against tumor cells in vitro and in vivo. In an attempt to elucidate the signalig mechanisms that regulate TCR-induced iNKT cell responses, I recently observed that immunoglobulin superfamily receptors, CD2 and 2B4 differentially regulate murine iNKT cell cytotoxicity. Specifically, Cd2-/- iNKTs completely failed to kill tumor targets while 2b4-/- iNKTs exhibited significantly enhanced cytolysis. Based upon these findings, I hypothesize that CD2 is a positive and 2B4 a negative regulator of TCR-induced iNKT cell functions. In this K22 proposal, I will build upon these new and exciting observations by further exploring the roles of CD2 and 2B4 in iNKT cell-mediated tumor clearance in vivo (Aim 1a) and iNKT cell immuno-stimulatory functions (cytokine production and activation of other immune cells) in vitro and in vivo (Aim 1b). Additionally, I will also examine the roles of these receptors in human iNKT cell activation, proliferation, cytokine production and anti- tumor responses in vitro (Aim 1c). To dissect the mechanistic basis by which these molecules regulate iNKT cell cytotoxicity, I will assess how disruption of CD2 or 2B4 signaling affects iNKT cell immunological synapse formation and maturation (Aim 2a). CD2 and 2B4 both bind to their ligand, CD48 but with different affinities. Furthermore, CD2 and 2B4 have different cytoplasmic tails, which are likely t confer distinct signaling functions. Therefore, I will delineate whether CD2 and 2B4 exert opposing roles by inducing distinct intracellular signals (Aim 2b) and/or by competing with one another for CD48 binding (Aim 2c). As CD1d (the ligand for the invariant TCR) and CD48 (the ligand for CD2 and 2B4) are both widely expressed on hematopoietic tumors, further elucidation of the mechanisms by which CD2 and 2B4 regulate TCR-induced iNKT cell anti- tumor activity is of significant scientific and clinical importance. These studies will facilitate a better understanding of iNKT cell biology and provide insights into how the anti-tumor activities of iNKT cells can be harnessed in a therapeutically relevant manner. To enable the successful completion of these studies and facilitate my scientific and career development, I have established critical collaborations and a scientific advisory committee that includes Drs. Stephan Grupp, Jordan Orange and Taku Kambayashi, all experts in their respective fields of investigation. I will take advantage of the intellectual strength and academic track record of my mentor and scientific advisory committee members, and the robust availability of expertise, facilities, and resources offered at The Children's Hospital of Philadelphia and the University of Pennsylvania to accomplish the training program outlined in this proposal.

描述（由申请人提供）：不变自然杀伤 T (iNKT) 细胞是参与宿主对癌症免疫的先天样 T 淋巴细胞。尽管人们认识到 iNKT 细胞可以促进抗肿瘤免疫反应，但关于这些细胞如何识别肿瘤细胞并对其做出反应，仍然存在许多问题。这种信息的缺乏阻碍了新型且可能更有效的基于 iNKT 细胞的癌症免疫疗法的开发。我的研究表明，原代小鼠和人类 iNKT 细胞在体外和体内表现出强大的 T 细胞受体 (TCR) 诱导的针对肿瘤细胞的细胞溶解活性。为了阐明调节 TCR 诱导的 iNKT 细胞反应的信号机制，我最近观察到免疫球蛋白超家族受体 CD2 和 2B4 差异调节小鼠 iNKT 细胞的细胞毒性。具体来说，Cd2-/- iNKT 完全无法杀死肿瘤靶点，而 2b4-/- iNKT 则完全无法杀死肿瘤靶标。表现出显着增强的细胞溶解作用。基于这些发现，我假设 CD2 是 TCR 诱导的 iNKT 细胞功能的正调节因子，2B4 是负调节因子。在这个 K22 提案中，我将在这些令人兴奋的新观察的基础上，进一步探索 CD2 和 2B4 在 iNKT 细胞介导的体内肿瘤清除中的作用（目标 1a）和 iNKT 细胞免疫刺激功能（细胞因子的产生和其他细胞因子的激活）。免疫细胞）体外和体内（目标 1b）。此外，我还将研究这些受体在体外人类 iNKT 细胞激活、增殖、细胞因子产生和抗肿瘤反应中的作用（目标 1c）。为了剖析这些分子调节 iNKT 细胞毒性的机制基础，我将评估 CD2 或 2B4 信号传导的破坏如何影响 iNKT 细胞免疫突触的形成和成熟（目标 2a）。 CD2 和 2B4 均与其配体 CD48 结合，但亲和力不同。此外，CD2 和 2B4 具有不同的细胞质尾部，这可能赋予不同的信号传导功能。因此，我将描述 CD2 和 2B4 是否通过诱导不同的细胞内信号（目标 2b）和/或通过相互竞争 CD48 结合（目标 2c）来发挥相反的作用。由于CD1d（不变TCR的配体）和CD48（CD2和2B4的配体）均在造血肿瘤中广泛表达，因此进一步阐明CD2和2B4调节TCR诱导的iNKT细胞抗肿瘤活性的机制具有重要意义。具有重要的科学和临床意义。这些研究将有助于更好地了解 iNKT 细胞生物学，并深入了解如何以治疗相关的方式利用 iNKT 细胞的抗肿瘤活性。为了成功完成这些研究并促进我的科学和职业发展，我建立了重要的合作关系和一个包括 Drs. 的科学咨询委员会。 Stephan Grupp、Jordan Orange 和 Taku Kambayashi 都是各自研究领域的专家。我将利用我的智力和学术优势我的导师和科学咨询委员会成员的跟踪记录，以及费城儿童医院和宾夕法尼亚大学为完成本提案中概述的培训计划提供的专业知识、设施和资源的强大可用性。

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）

Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody.

NKTT320 是一种新型、不变、自然杀伤 T 细胞激活的人源化单克隆抗体，其癌症免疫治疗潜力。

DOI：
发表时间：
2020-06-17
期刊：
影响因子：
5.6
作者：
Patel, Nishant P;Guan, Peng;Bahal, Devika;Hashem, Tanwir;Scheuplein, Feli;Schaub, Robert;Nichols, Kim E;Das, Rupali
通讯作者：
Das, Rupali

SLAM-SAP-Fyn: Old Players with New Roles in iNKT Cell Development and Function.

SLAM-SAP-Fyn：iNKT 细胞发育和功能中的老玩家扮演新角色。