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

• 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
• 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

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).

项目摘要 免疫检查点阻滞疗法诱导耐用的抗肿瘤免疫反应，并改变了护理 用于晚期癌症，包括转移性疾病。但是，大多数患者几乎没有临床益处 从治疗。导致临床结果不佳的重要因素是免疫渗透肿瘤表型。在这个 状态，即使在存在抗肿瘤免疫细胞的情况下，癌细胞仍能抵抗清除。有一个 （1）确定驱动免疫渗透肿瘤表型和（2）治疗的机制的临界需求 将这些靶向与免疫切克点抑制剂结合使用，以刺激抗肿瘤免疫。 该提案是由两个意外发现的动机：首先，肌肉盲蛋白（MBNL） - T细胞介导的癌细胞杀死所必需的RNA结合蛋白家族。而mbnl 在神经肌肉疾病的背景下，蛋白质一直非常研究，它们对肿瘤的贡献 尚未探索免疫相互作用。该建议利用了丰富的知识 有关MBNL调节的RNA处理，以确定RNA代谢在肿瘤免疫中的新作用 逃避。其次，MBNL成绩单受到反复的，泛伴奏的失误，这是密切相关的 具有免疫渗透表型。这种剪接介导的疾病机制提供了独特的机会 将酶线切换寡核苷酸疗法与免疫检查点抑制剂结合使用 刺激抗肿瘤免疫。 AIM 1使用细胞测定和基因组学来确定 MBNL参与干扰素信号传导，抗原表现和免疫异常中的基因表达 癌症。 AIM 2使用合成性肿瘤模型，高维流式细胞术和同工型分离 功能研究以确定MBNL剪接同工型如何调节RNA代谢以促进肿瘤生长 并塑造肿瘤免疫微环境。 AIM 3使用临床前肿瘤模型来检验假设 基于寡核苷酸的校正癌症相关的MBNL失误将改善肿瘤对 免疫检查点抑制剂。 在整个建议中，MBNL及其各自的剪接同工型被用作模型系统，但 申请人的长期目标是建立他的独立研究计划，旨在定义更一般的研究 RNA介导的免疫避免和免疫疗法耐药性的原理。为了实现这些目标， 提案概述了一项职业发展计划，以增加申请人在RNA介导的疾病和 功能性基因组学通过肿瘤免疫学和临床前治疗模型中的培训。这个培训将是 申请人的精神（癌症中RNA剪接）的完整专业知识（肿瘤）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）。