Role of NF-κB c-Rel in regulating Natural Killer cell anti-tumor functions

NF-κB c-Rel 在调节自然杀伤细胞抗肿瘤功能中的作用

• 批准号: 9758344
• 负责人: Yorleny M Vicioso
• 金额: $ 4.07万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758344
• 关键词: Address; Antiviral Agents; Binding; CRISPR/Cas technology; Cancer Patient; Cell physiology; Cells; Cytolysis; Data; Development; Exhibits; Functional disorder; Genetic; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granzyme; Host Defense Mechanism; Human; Immune; Immune system; Immunologic Surveillance; Impairment; Interleukin-15; Interleukin-2; Invaded; Knock-out; Knockout Mice; Lead; Leukocytes; Light; Liquid substance; Lymphocyte; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Myelogenous; Natural Killer Cells; Patients; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signaling Molecule; Solid; T-Cell Proliferation; Thymus Gland; Virus; acute lymphoblastic leukemia cell; cancer cell; cancer therapy; cell killing; cell transformation; cytokine; cytotoxic; cytotoxicity; exhaust; gain of function; improved; inhibitor/antagonist; mRNA Expression; melanoma; mouse model; neoplastic cell; novel; overexpression; pathogen; perforin; promoter; protein expression; small molecule; small molecule inhibitor; transcription factor; tumor

Project Summary/Abstract The immune system serves as a host-defense mechanism against invading pathogens and transformed cells through an intricate network of signaling molecules and specialized cells. Natural Killer (NK) cells are cytotoxic lymphocytes that kill virus-infected and cancer cells. They are an integral component of tumor-immune surveillance. However, Natural Killer cells from cancer patients are rendered dysfunctional1-10. Finding key factors that regulate NK cell cytotoxic function is vital to understand the mechanistic alterations leading into NK cell dysfunction in cancer. Various studies show that NK cell cytotoxicity can be mediated by cytokines including: IL- 2, GM-CSF, IL-15, IL-21, and TGF-β11-20, all of which are regulated by NF-κB c-Rel21-23. NF-κB c- Rel is a transcription factor that is constitutively expressed in myeloid and lymphocytic lineages24. Although c-Rel has been reported to promote T cell proliferation and cytokine production24-27, the role of c-Rel in NK cells remains unknown. Preliminary studies utilizing purified murine WT and c- Rel-/- NK cells, show that deficiency in c-Rel expression results in reduced perforin expression and impaired anti-tumor function in murine NK cells. Similarly, inhibition of c-Rel with specific small molecule inhibitor, lead to decreased perforin expression and impaired anti-tumor cytotoxicity of human NK cells. We therefore seek to define the role of c-Rel in regulating mouse and human NK cell anti-tumor cytotoxic activity. The first aim will define the role of c-Rel in regulating NK cell cytotoxic function. The second aim will investigate the mechanism by which c-Rel regulates NK cells ability to kill tumor cells. Completion of these aims will define the mechanism-driven c-Rel regulation of NK cell cytotoxic function.

项目摘要/摘要 免疫系统是一种反对入侵病原体和的宿主防御机制 通过错综复杂的信号分子和专门细胞网络转化细胞。 天然杀伤（NK）细胞是细胞毒性淋巴细胞，可杀死感染病毒和癌细胞。他们 是肿瘤免疫监测的组成部分。但是，来自 癌症患者的功能失调1-10。查找调节NK细胞细胞毒性的关键因素 功能对于理解导致NK细胞功能障碍的机械变化至关重要 癌症。各种研究表明，NK细胞细胞毒性可以由细胞因子介导：IL- 2，GM-CSF，IL-15，IL-21和TGF-β11-20，所有这些都由NF-κBC-REL21-23调节。 NF-κBc- RER是在髓样和淋巴细胞谱系中始终表达的转录因子24。 尽管据报道C-Rel促进T细胞增殖和细胞因子产生24-27，但 C-Rel在NK细胞中的作用仍然未知。使用纯化的鼠WT和C-的初步研究 REL - / - NK细胞表明，C-Rel表达缺乏会导致穿孔蛋白表达降低和 鼠NK细胞中抗肿瘤功能受损。同样，用特定小的抑制c-rel抑制 分子抑制剂，导致穿孔蛋白表达降低和抗肿瘤细胞毒性受损 人NK细胞。因此，我们试图定义C-Rel在调节小鼠和人类中的作用 NK细胞抗肿瘤细胞毒性活性。第一个目标将定义C-Rel在调节NK单元中的作用 细胞毒性功能。第二个目标将研究C-Rel调节NK的机制 细胞能够杀死肿瘤细胞的能力。这些目标的完成将定义机构驱动的C-REL 调节NK细胞细胞毒性功能。