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Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells

NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向

基本信息

批准号：
10520016
负责人：
Jianhua Yu
金额：
$ 43.68万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520016
关键词：
AKT Signaling Pathway Binding Binding Proteins Binding Sites Blood Cell Nucleus Cell Survival Cell Therapy Cell physiology Cells Cellular Stress Cellular biology Cities Clinic Combined Modality Therapy Complex Data Deubiquitination Development Down-Regulation Educational workshop Effector Cell Engineering Enzymes FOXO1A gene Foundations Gene Expression Gene Expression Regulation Genes Haplotypes Homeostasis Human IFNG gene Immune response Immunity Immunology Immunotherapy Impairment In Vitro Infusion procedures Inositol Interferon Type II Interleukin-15 Journals KLRD1 gene Longevity Lymphoid Cell Malignant Neoplasms Mediating Messenger RNA Molecular Multiple Myeloma Mus Natural Killer Cell Immunotherapy Natural Killer Cell toxicity Natural Killer Cells Nature Nuclear Protein Oncogenic Viruses Pathway interactions Patients Play Population Pre-Clinical Model Process Production Proliferating Protein Splicing Proteins Proto-Oncogene Proteins c-akt Published Comment Publishing RNA Splicing Recurrent disease Reporting Resistance Role Signal Pathway Signal Transduction Signaling Protein Testing Time Transforming Growth Factor beta Translating Tumor-infiltrating immune cells Virus Work XBP1 gene anti-PD-1 anti-PD-L1 cancer immunotherapeutics cancer immunotherapy cancer therapy chimeric antigen receptor conditional knockout cytokine cytotoxicity human data improved improved outcome in vivo inhibitor innovation insight interleukin-15 receptor migration neoplastic cell new therapeutic target novel novel strategies prevent promoter protein expression receptor recruit trafficking transcription factor tumor tumor eradication

项目摘要

NK cells are the first line of defense against tumor cells. We recently developed CAR NK cells for the treatment of multiple myeloma (MM), which demonstrates improved anti-MM activity. However, challenges still exist for NK cell- based cancer immunotherapy: some tumor cells are resistant to cytotoxicity of NK cells that have a short life span after infusion into patients. Thus, further understanding of NK cells will be critical to better harness this population for immunotherapy. Our data recently published in Nature Immunology show that an important transcription factor, XBP1s, encoded by an unconventionally spliced mRNA of X-box binding protein (XBP1), positively regulates NK cell survival and effector functions. XBP1s regulates NK cell cytotoxicity and GZMB gene expression via direct promoter binding. XBP1s physically interacts with T-BET, a master regulator in NK cells, suggesting that XBP1s can recruit T-BET to the promoters of target genes. This discovery fills a current gap in the field, as T-BET is known to positively regulate the expression of GZMB despite lacking direct T-BET binding sites on the GZMB promoter. Moreover, IL-15, one of the most important cytokines regulating NK cell survival, development, and effector functions, activates AKT signaling to increase stability of XBP1s protein via deubiquitination, leading to XBP1s nuclear accumulation. Consistent with these human data, conditional knockout of Xbp1 in mice shows a decreased number of NK cells and impaired NK cell anti-tumor activity. We believe that we have identified a novel IL-15-AKT- XBP1s signaling pathway that plays key roles in regulating multiple aspects of NK cell biology. Thus, our overall hypothesis is that this IL-15-AKT-XBP1s signaling pathway newly identified by our group positively regulates NK cell survival and effector functions and can be utilized to improve NK cell or CAR NK cell- based cancer immunotherapy. We propose mechanistic studies regarding how XBP1s regulates NK cell survival and effector functions. We also propose combinational therapies of IL-15/IL-15Rα with CS1-CAR NK cells or with B-I09, a novel drug targeting XBP1 splicing to XBP1s that has strong activity in treating various cancers including MM. IL-15/IL-15Rα can selectively stabilize the XBP1s protein and prevent B-I09-mediated downregulation of XBP1s and the associated inhibition of functions in NK cells. We will engineer CS1-CAR NK cells to express IL- 15/IL-15Rα or XBP1s to have enhanced in vivo persistence of these cells for continuous tumor eradication. Three Aims are proposed. Aim 1: Study the mechanism and functional consequences of enhanced XBP1s protein expression levels via IL-15-AKT signaling in NK cells. Aim 2: Study whether and/or how XBP1s regulates NK cell survival, proliferation, and trafficking. Aim 3: Study the role of XBP1s in combination therapies of IL-15/IL-15Rα with a novel drug targeting XPB1s, B-I09, and/or with CS1-CAR NK cells for the treatment of MM. Our project is significant and timely as IL-15 and IL-15/IL-15Rα are top agents for cancer immunotherapy and are being actively tested in the clinic. Our studies will lead to new insights into NK cell biology, improve outcomes for NK cell-based immunotherapy, and facilitate developing innovative cancer immunotherapeutics.

NK细胞是对抗肿瘤细胞的第一道防线。我们最近开发了CAR NK细胞用于治疗多发性骨髓瘤（MM），其表现出改善的抗MM活性。然而，NK细胞仍然存在挑战- 基于癌症免疫疗法：一些肿瘤细胞对寿命短的NK细胞的细胞毒性具有抗性输注到患者体内后。因此，进一步了解NK细胞将是至关重要的，以更好地利用这一群体用于免疫治疗。我们最近发表在《自然免疫学》上的数据表明，一种重要的转录因子， X-box结合蛋白（X-box binding protein，XBP 1）基因编码的XBP 1 s对NK细胞具有正调控作用细胞存活和效应子功能。XBP 1 s通过直接调控NK细胞毒性和GZMB基因表达启动子结合XBP 1 s与NK细胞中的主要调节因子T-BET发生物理相互作用，这表明XBP 1 s 可以将T-BET募集到靶基因的启动子上。这一发现填补了该领域目前的空白，因为T-BET被称为尽管在GZMB启动子上缺乏直接的T-BET结合位点，但仍能正向调节GZMB的表达。此外，IL-15是调节NK细胞存活、发育和效应细胞的最重要的细胞因子之一，功能，激活AKT信号传导，通过去泛素化增加XBP 1 s蛋白的稳定性，导致XBP 1 s 核积累与这些人类数据一致，小鼠中Xbp 1的条件性敲除显示出降低的 NK细胞数量和NK细胞抗肿瘤活性受损。我们相信我们已经发现了一种新的IL-15-AKT， XBP 1 s信号通路在调节NK细胞生物学的多个方面发挥关键作用。因此，我们的总体假设我们组新发现的IL-15-AKT-XBP 1 s信号通路调节NK细胞存活和效应子功能，并可用于改善NK细胞或CAR NK细胞- 癌症免疫疗法。我们提出了关于XBP 1 s如何调节NK细胞存活的机制研究和效应器功能。我们还提出了IL-15/IL-15 R α与CS 1-CAR NK细胞或与 B-I 09是一种靶向XBP 1剪接到XBP 1 s的新型药物，在治疗各种癌症方面具有很强的活性，包括毫米IL-15/IL-15 R α可以选择性地稳定XBP 1 s蛋白，并阻止B-I 09介导的 XBP 1 s和NK细胞功能的相关抑制。我们将设计CS 1-CAR NK细胞来表达IL-10。 15/IL-15 R α或XBP 1增强了这些细胞的体内持久性，可持续根除肿瘤。三提出了目标。目的1：研究增强型XBP 1 s蛋白的作用机制和功能后果通过NK细胞中的IL-15-AKT信号传导的表达水平。目的2：研究XBP 1 s是否和/或如何调节NK细胞生存、扩散和贩运。目的3：研究XBP 1 s在IL-15/IL-15 R α联合治疗中的作用用靶向XPB 1 s、B-I 09和/或CS 1-CAR NK细胞的新型药物治疗MM。我们的项目是 IL-15和IL-15/IL-15 R α是癌症免疫治疗的顶级药物，在诊所测试。我们的研究将导致对NK细胞生物学的新见解，改善基于NK细胞的治疗结果，免疫疗法，并促进开发创新的癌症免疫疗法。