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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).

项目概要免疫检查点阻断疗法可诱导持久的抗肿瘤免疫反应，并改变了护理方式用于晚期癌症，包括转移性疾病。然而，大多数患者几乎没有或根本没有临床获益来自治疗。导致不良临床结果的一个重要因素是免疫逃避的肿瘤表型。在这个状态，即使存在抗肿瘤免疫细胞，癌细胞仍然难以清除。有一个迫切需要（1）确定驱动免疫逃避肿瘤表型的机制和（2）治疗将这些药物与免疫检查点抑制剂结合起来，以刺激抗肿瘤免疫力。这一提议的动机是两个意想不到的发现：首先，肌盲样蛋白（MBNL）—— RNA 结合蛋白家族——是 T 细胞介导的癌细胞杀伤所必需的。而MBNL 蛋白质已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尚未被探索。该提案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发生的、与癌症密切相关的泛癌错误剪接。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转换寡核苷酸疗法与免疫检查点抑制剂相结合，刺激抗肿瘤免疫力。目标 1 使用细胞分析和基因组学来确定 MBNL 参与免疫逃避中的干扰素信号传导、抗原呈递和基因表达癌症。目标 2 使用同基因肿瘤模型、高维流式细胞术和异构体分离功能研究以确定 MBNL 剪接异构体如何调节 RNA 代谢以促进肿瘤生长并塑造肿瘤免疫微环境。目标 3 使用临床前肿瘤模型来检验假设基于寡核苷酸的癌症相关 MBNL 错误剪接纠正将改善肿瘤的反应免疫检查点抑制剂。虽然 MBNL 及其各自的剪接亚型在整个提案中被用作模型系统，申请人的长期目标是建立他的独立研究计划，旨在定义更普遍的 RNA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，这提案概述了职业发展计划，以加强申请人在 RNA 介导疾病方面的培训，以及功能基因组学，接受肿瘤免疫学和临床前治疗模型的培训。此次培训将申请人的导师（癌症中的 RNA 剪接）、共同导师（肿瘤免疫学）、合作者（临床前治疗研究、MBNL 调节的 RNA 代谢）和科学顾问团队（免疫学、干扰素信号传导）。