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Biological and therapeutic consequences of RNA dysregulation in cancer immune evasion

RNA 失调在癌症免疫逃避中的生物学和治疗后果

基本信息

批准号：
10457190
负责人：
JAMES Douglas THOMAS
金额：
$ 3.16万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457190
关键词：
Advanced Malignant Neoplasm Advisory Committees Alternative Splicing Antigen Presentation Antigen Presentation Pathway Automobile Driving Award Biological Biological Assay Biological Models Biological Response Modifier Therapy Biopsy Cancer Biology Cancer Patient Caring Cells Cellular Assay Characteristics Clinical Coculture Techniques Collaborations Detection Development Development Plans Disease Event Exhibits Family Flow Cytometry Foundations Gene Expression Gene Silencing Genetic Genomics Goals Human Immune Immune Evasion Immune checkpoint inhibitor Immune system Immunologics Immunology Immunooncology Immunotherapy Individual Interferons Knock-out Knowledge Malignant Neoplasms Measures Mediating Mentors Methodology Modality Modeling Molecular Mutation Nature Neuromuscular Diseases Nuclear Oligonucleotides Outcome Patients Phase Phenotype Physiological Positioning Attribute Pre-Clinical Model Process Protein Isoforms Proteins RNA RNA Processing RNA Splicing RNA metabolism RNA-Binding Proteins RNA-targeting therapy Recurrence Research Research Training Resistance Role Shapes Signal Transduction Source System T-Lymphocyte Testing Therapeutic Therapeutic Intervention Therapeutic Studies Training Transcript Treatment Efficacy Tumor Escape Tumor Immunity Tumor-infiltrating immune cells Work anti-tumor immune response base cancer cell cancer immunotherapy career development checkpoint therapy efficacy testing exhaustion exome sequencing functional genomics genome-wide high dimensionality immune checkpoint blockade immune clearance immunogenicity improved in vivo innovation non-genetic novel novel therapeutics pre-clinical programs response targeted treatment therapeutic RNA therapeutic target tool transcriptomics tumor tumor growth tumor immunology tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Immune checkpoint blockade therapy induces durable anti-tumor immune responses and has transformed care for advanced cancer, including metastatic disease. However, most patients derive little or no clinical benefit from therapy. An important contributor to poor clinical outcomes is an immune-evasive tumor phenotype; in this state, cancer cells remain resistant to clearance even in the presence of anti-tumor immune cells. There is a critical need to (1) identify mechanisms driving an immune-evasive tumor phenotype and (2) therapeutically target these in combination with immune checkpoint inhibitors to stimulate anti-tumor immunity. This proposal is motivated by two unexpected discoveries: First, Muscleblind-like proteins (MBNLs) — a family of RNA-binding proteins — are required for T cell-mediated killing of cancer cells. While MBNL proteins have been exhaustively studied in the context of neuromuscular disease, their contributions to tumor- immune interactions have not been explored. This proposal takes advantage of the wealth of knowledge regarding MBNL-regulated RNA processing to determine novel roles for RNA metabolism in tumor immune evasion. Second, MBNL transcripts are subject to recurrent, pan-cancer mis-splicing that is strongly associated with an immune-evasive phenotype. This splicing-mediated disease mechanism presents a unique opportunity to use splice-switching oligonucleotide therapies, in combination with immune checkpoint inhibitors, to stimulate anti-tumor immunity. Aim 1 uses cellular assays and genomics to determine the mechanistic basis of MBNL’s involvement in interferon signaling, antigen presentation, and gene expression in immune-evasive cancers. Aim 2 uses syngeneic tumor models, high-dimensional flow cytometry, and isoform separation-of- function studies to determine how MBNL splice isoforms regulate RNA metabolism to promote tumor growth and shape the tumor-immune microenvironment. Aim 3 uses preclinical tumor models to test the hypothesis that oligonucleotide-based correction of cancer-associated MBNL mis-splicing will improve tumor response to immune checkpoint inhibitors. While MBNLs and their individual splice isoforms are used as model systems throughout this proposal, the applicant’s long-term goal is to establish his independent research program aimed at defining more general principles of RNA-mediated immune evasion and immunotherapy resistance. To achieve these goals, this proposal outlines a career development plan to augment the applicant’s training in RNA-mediated disease and functional genomics with training in tumor immunology and preclinical therapeutic models. This training will be facilitated by the complementary expertise of the applicant’s mentor (RNA splicing in cancer), co-mentor (tumor immunology), collaborators (preclinical therapeutic studies, MBNL-regulated RNA metabolism), and scientific advisory team (immunology, interferon-signaling).

项目总结免疫检查点阻断疗法诱导持久的抗肿瘤免疫反应并改变了治疗用于晚期癌症，包括转移性疾病。然而，大多数患者几乎或根本得不到临床益处。从治疗中脱身。临床结果不佳的一个重要因素是免疫逃避型肿瘤表型；即使在存在抗肿瘤免疫细胞的情况下，癌细胞仍然对清除具有抵抗力。有一个迫切需要(1)确定免疫逃逸肿瘤表型的驱动机制和(2)治疗靶向这些与免疫检查点抑制剂相结合，以刺激抗肿瘤免疫。这一提议是由两个意想不到的发现推动的：第一，类蝇毒样蛋白(MBNLS)- 一组RNA结合蛋白是T细胞介导的杀伤癌细胞所必需的。而MBNL 蛋白质已经在神经肌肉疾病的背景下进行了详尽的研究，它们对肿瘤的贡献- 免疫相互作用还没有被探索过。这项建议利用了丰富的知识。关于MBNL调节的RNA加工，以确定RNA代谢在肿瘤免疫中的新作用逃避。其次，MBNL转录本容易发生反复的、泛癌的错误剪接，这与MBNL转录本有很强的相关性具有免疫逃避表型。这种剪接介导的疾病机制提供了一个独特的机会使用剪接切换寡核苷酸疗法，结合免疫检查点抑制剂，以激发抗肿瘤免疫力。AIM 1使用细胞分析和基因组学来确定 MBNL参与免疫逃避中干扰素信号转导、抗原提呈和基因表达癌症。AIM 2使用同基因肿瘤模型、高维流式细胞术和异构体分离确定MBNL剪接异构体如何调节RNA代谢促进肿瘤生长的功能研究塑造肿瘤免疫微环境。目标3使用临床前肿瘤模型来检验这一假说基于寡核苷酸的癌症相关MBNL错误剪接的纠正将改善肿瘤对免疫检查点抑制剂。虽然MBNLS及其各自的剪接异构体在本提案中用作模型系统，申请者的长期目标是建立他的独立研究计划，旨在定义更一般的核糖核酸介导的免疫逃避和免疫治疗抵抗的原理。为了实现这些目标，这建议书概述了职业发展计划，以加强申请者在RNA介导性疾病和具有肿瘤免疫学和临床前治疗模式培训的功能基因组学。这次培训将是由申请人的导师(癌症中的RNA剪接)、共同导师(肿瘤)的互补专业知识促进免疫学)、合作者(临床前治疗研究、MBNL调节的RNA代谢)和科学咨询团队(免疫学、干扰素信号传递)。