Immune Evasion by Multiple Myeloma: Role of the Rho Kinase Signaling Pathway

多发性骨髓瘤的免疫逃避：Rho 激酶信号通路的作用

• 批准号: 8461126
• 负责人: Randy R Brutkiewicz
• 金额: $ 30.43万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-19 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461126
• 关键词: Actins; Address; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmunity; Biological Models; Blood; Cell Survival; Cell physiology; Cells; Characteristics; Communicable Diseases; Cytoskeleton; Development; Diagnosis; Disease; Disease Progression; Goals; Hematopoietic Neoplasms; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; In Vitro; Indium; Invaded; Laboratories; Learning; Lipids; MAPK8 gene; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Modeling; Molecular; Multiple Myeloma; Mus; Natural Immunity; Neoplasm Metastasis; Pathway interactions; Patients; Play; Publishing; Rho-associated kinase; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Surface; System; T cell response; Testing; TimeLine; Work; adaptive immunity; cancer cell; cell transformation; human disease; in vivo; in vivo Model; killer T cell; metaplastic cell transformation; neoplastic cell; pathogen; polymerization; pre-clinical; prevent; research study; scaffold; stress-activated protein kinase 1; tumor; vaccine development

DESCRIPTION (provided by applicant): The innate immune response is the first line of defense against the threat of invading pathogens, as well as the development of cellular transformation, with the latter ultimately leading to cancer. Two major players in innate immunity are the lipid antigen presenting CD1d molecules, and the immunoregulatory NKT cells that recognize them. Evidence from multiple laboratories suggests that NKT cells can regulate adaptive immunity, thus serving as a bridge between the innate and adaptive immune responses. From the perspective of a CD1d+ tumor, being able to prevent NKT cell recognition would thus thwart overall antitumor immunity. Multiple myeloma (MM) is a devastating disease, with patients surviving from a few months to at most several years following diagnosis. Even with new treatments emerging, MM is still incurable. Thus, it is important to understand, at a fundamental level, the characteristics of MM cells that permit it to persist in a host. Recent evidence has suggested that NKT cell responses in MM patients are impaired and that MM cells express surface CD1d molecules. Additional work has shown that cell signaling pathways contribute to MM cell survival, metastasis and immune evasion. The ability of a blood tumor cell to avoid recognition by the host's antitumor immunosurveillance system is an obstacle to treatments that can prevent (or control) the development of systemic tumor. We and others have shown that the innate immune response, specifically, CD1d-mediated lipid antigen presentation to NKT cells, is an important component of the antitumor immune response against blood cancers. Recently, we have demonstrated that several signal transduction pathways regulate antigen presentation by CD1d, as well as by MHC class II molecules. It is known that a variety of tumors alter these cell signaling pathways. The overall goal of this application is to understand in more detail the mechanisms by which CD1d-mediated antigen presentation is regulated normally and how CD1d+ myeloma tumor cells are impaired in their ability to present antigen to NKT cells. Our hypothesis is that ROCK negatively regulates CD1d-mediated antigen presentation by two means: 1. Control of actin polymerization and 2. Activation of JNK, which reduces antigen presentation by CD1d, independently of the actin cytoskeleton. To test this hypothesis, the following specific aims are proposed: 1. Dissect in detail the mechanism(s) by which the ROCK pathway regulates antigen presentation by CD1d to NKT cells; 2. Determine the role of the ROCK pathway in controlling CD1d-mediated antigen presentation in human multiple myeloma cells; 3. Analyze the role of the ROCK pathway in the antitumor immune response by NKT cells in vivo. Increasing our understanding of the molecular mechanisms that govern antigen presentation by CD1d has applications not only in cancer, but also in infectious diseases, vaccine development and autoimmune diseases.

描述（由申请人提供）：先天免疫反应是抵御入侵病原体威胁的第一道防线，也是细胞转化发展的第一道防线，后者最终导致癌症。先天免疫中的两个主要参与者是脂质抗原呈递 CD1d 分子和识别它们的免疫调节 NKT 细胞。来自多个实验室的证据表明，NKT 细胞可以调节适应性免疫，从而充当先天免疫反应和适应性免疫反应之间的桥梁。从 CD1d+ 肿瘤的角度来看，能够阻止 NKT 细胞识别将阻碍整体抗肿瘤免疫。多发性骨髓瘤 (MM) 是一种毁灭性的疾病，患者在诊断后只能存活几个月到最多几年。即使出现了新的治疗方法，多发性骨髓瘤仍然无法治愈。因此，从根本上了解 MM 细胞允许其在宿主体内持续存在的特征非常重要。最近的证据表明 MM 患者的 NKT 细胞反应受损，并且 MM 细胞表达表面 CD1d 分子。其他工作表明，细胞信号传导途径有助于 MM 细胞存活、转移和免疫逃避。血液肿瘤细胞避免被宿主抗肿瘤免疫监视系统识别的能力是预防（或控制）全身性肿瘤发展的治疗的障碍。我们和其他人已经证明，先天免疫反应，特别是 CD1d 介导的脂质抗原呈递给 NKT 细胞，是针对血癌的抗肿瘤免疫反应的重要组成部分。最近，我们证明了几种信号转导途径通过 CD1d 以及 MHC II 类分子调节抗原呈递。众所周知，多种肿瘤会改变这些细胞信号传导途径。本申请的总体目标是更详细地了解 CD1d 介导的抗原呈递正常调节的机制，以及 CD1d+ 骨髓瘤肿瘤细胞向 NKT 细胞呈递抗原的能力如何受损。我们的假设是，ROCK 通过两种方式负调节 CD1d 介导的抗原呈递：1. 控制肌动蛋白聚合；2. 激活 JNK，减少 CD1d 的抗原呈递，独立于肌动蛋白细胞骨架。为了检验这一假设，提出以下具体目标： 1. 详细剖析 ROCK 通路调节 CD1d 向 NKT 细胞呈递抗原的机制； 2.确定ROCK通路在控制人多发性骨髓瘤细胞中CD1d介导的抗原呈递中的作用； 3.分析ROCK通路在体内NKT细胞抗肿瘤免疫反应中的作用。加深我们对 CD1d 控制抗原呈递的分子机制的了解不仅适用于癌症，还适用于传染病、疫苗开发和自身免疫性疾病。