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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