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：
10304873
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/10304873
关键词：
AKT Signaling Pathway Binding Binding Proteins Binding Sites Blood Cell Nucleus Cell Survival Cell Therapy Cell physiology Cells Cellular Stress Response Cellular biology Cellular immunotherapy Cities Clinic Combined Modality Therapy Complex Data Deubiquitination Development Down-Regulation Educational workshop Effector Cell Engineering Enzymes FOXO1A gene Factor X 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 toxicity Natural Killer Cells Nature Nuclear Protein Oncogenic Viruses Pathway interactions Patients Play Population Pre-Clinical Model Process Production 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 Ubiquitination Virus Work XBP1 gene anti-PD-1 anti-PD-L1 base cancer cell 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细胞是针对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），表现出改善的抗MM活性。但是，NK细胞仍然存在挑战 - 基于癌症的免疫疗法：某些肿瘤细胞对NK细胞的细胞毒性具有抗性输入患者后。这是对NK细胞的进一步了解对于更好地利用这一人群至关重要用于免疫疗法。我们最近在自然免疫学上发表的数据表明，一个重要的转录因子， XBP1，由X-box结合蛋白（XBP1）的非常规剪接mRNA编码，对NK进行积极调节细胞存活和效应子功能。 XBP1通过直接调节NK细胞细胞毒性和GZMB基因表达启动子结合。 XBP1与NK细胞中的主调节器T-Bet物理相互作用，表明XBP1S 可以将T-BET募集到靶基因的启动子。该发现填补了现场的当前空白，因为T-bet已知为了积极调节GZMB目的地的表达，缺乏GZMB启动子上的直接T-Bet结合位点。此外，IL-15是调节NK细胞存活，发育和效应子的最重要的细胞因子之一功能，激活Akt信号传导以通过去泛素化提高XBP1S蛋白的稳定性，从而导致XBP1S 核积累。与这些人类数据一致，小鼠中XBP1的有条件敲除显示了一个下降的 NK细胞的数量和NK细胞抗肿瘤活性受损。我们相信我们已经确定了一种新颖的IL-15-akt- XBP1信号通路在调节NK细胞生物学的多个方面中起关键作用。那是我们的整体假设是我们组正肯定地确定的这个IL-15-AKT-XBP1S信号通路调节NK细胞的存活和效应子功能，可用于改善NK细胞或CAR NK细胞 - 基于癌症免疫疗法。我们提出了有关XBP1如何调节NK细胞存活的机械研究和效应子功能。我们还提出了IL-15/IL-15Rα与CS1-CAR NK细胞的组合疗法或 B-I09，一种针对XBP1剪接XBP1的新型药物，在治疗包括包括毫米。 IL-15/IL-15Rα可以选择性地稳定XBP1S蛋白，并防止B-I09介导的下调 XBP1和NK细胞中功能的相关抑制作用。我们将设计CS1级NK细胞以表达IL- 15/IL-15Rα或XBP1可以增强这些细胞的体内持久性，以消除肿瘤。三提出了目标。目标1：研究增强XBP1蛋白的机制和功能后果 NK细胞中通过IL-15-AKT信号传导的表达水平。 AIM 2：研究XBP1是否调节NK细胞和/或如何生存，扩散和贩运。 AIM 3：研究XBP1在IL-15/IL-15Rα联合疗法中的作用具有针对XPB1的新型药物，B-I09和/或与CS1碳NK细胞进行MM的治疗。我们的项目是大量和及时的IL-15和IL-15/IL-15Rα是癌症免疫疗法的顶级药物，并且正在积极进行在诊所进行了测试。我们的研究将导致对NK细胞生物学的新见解，改善基于NK细胞的结果免疫疗法，并促进发展创新的癌症免疫治疗药。