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:10709187
- 负责人:
- 金额:$ 9.81万
- 依托单位:
- 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 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Advanced Malignant NeoplasmAdvisory CommitteesAlternative SplicingAntigen PresentationAntigen Presentation PathwayAutomobile DrivingAwardBiologicalBiological AssayBiological ModelsBiological Response Modifier TherapyBiopsyCancer BiologyCancer PatientCaringCellsCellular AssayCharacteristicsClinicalCoculture TechniquesCollaborationsDetectionDevelopmentDevelopment PlansDiseaseEventExhibitsFamilyFlow CytometryFoundationsGene ExpressionGene SilencingGeneticGenomicsGoalsHumanImmuneImmune EvasionImmune checkpoint inhibitorImmune systemImmunologicsImmunologyImmunooncologyImmunotherapyIndividualInterferonsKnock-outKnowledgeMalignant NeoplasmsMeasuresMediatingMentorsMethodologyModalityModelingMolecularMutationNatureNeuromuscular DiseasesNuclearOligonucleotidesOutcomePatientsPhasePhenotypePhysiologicalPositioning AttributePre-Clinical ModelProcessProtein IsoformsProteinsRNARNA ProcessingRNA SplicingRNA metabolismRNA-Binding ProteinsRNA-targeting therapyRecurrenceResearchResearch TrainingResistanceRoleShapesSignal TransductionSourceSystemT-LymphocyteTestingTherapeuticTherapeutic InterventionTherapeutic StudiesTrainingTranscriptTreatment EfficacyTumor EscapeTumor ImmunityTumor-infiltrating immune cellsWorkanti-tumor immune responsebasecancer cellcancer immunotherapycareer developmentcheckpoint therapyefficacy testingexhaustionexome sequencingfunctional genomicsgenome-widehigh dimensionalityimmune checkpoint blockadeimmune clearanceimmunogenicityimprovedin vivoinnovationnon-geneticnovelnovel therapeuticspre-clinicalprogramsresponsetargeted treatmenttherapeutic RNAtherapeutic targettooltranscriptomicstumortumor growthtumor immunologytumor-immune system interactionstumorigenesis
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).
项目摘要
免疫检查点阻断疗法可诱导持久的抗肿瘤免疫应答,并改变了护理
晚期癌症包括转移性疾病然而,大多数患者很少或根本没有临床获益
从治疗中。不良临床结果的一个重要因素是免疫逃避性肿瘤表型;在本研究中,
在这种状态下,即使存在抗肿瘤免疫细胞,癌细胞仍然对清除具有抗性。有一个
迫切需要(1)确定驱动免疫逃避性肿瘤表型的机制和(2)治疗
靶向这些与免疫检查点抑制剂组合以刺激抗肿瘤免疫。
这一提议的动机是两个意想不到的发现:第一,肌盲样蛋白(MBNL)-
RNA结合蛋白家族-是T细胞介导的杀死癌细胞所必需的。虽然MBNL
在神经肌肉疾病的背景下,蛋白质已经被详尽地研究,它们对肿瘤的贡献,
免疫相互作用尚未被探索。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
逃避第二,MBNL转录物易受复发性泛癌错误剪接的影响,
具有免疫逃避表型这种剪接介导的疾病机制提供了独特的机会
使用剪接转换寡核苷酸疗法,与免疫检查点抑制剂联合,
刺激抗肿瘤免疫。目的1使用细胞分析和基因组学来确定
MBNL参与免疫逃避性肿瘤的干扰素信号传导、抗原呈递和基因表达
癌的目的2使用同基因肿瘤模型,高维流式细胞术,
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。AIM 3使用临床前肿瘤模型来验证这一假设
基于阿糖胞苷的癌症相关MBNL错误剪接的校正将改善肿瘤对以下的反应:
免疫检查点抑制剂。
虽然MBNL和它们的单个剪接异构体在整个提议中用作模型系统,
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疗法抗性的原理。为了实现这些目标,
提案概述了职业发展计划,以加强申请人在RNA介导的疾病方面的培训,
功能基因组学与肿瘤免疫学和临床前治疗模型的培训。将培训以文件形式进行
在申请人导师(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
咨询团队(免疫学、干扰素信号)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES Douglas THOMAS其他文献
JAMES Douglas THOMAS的其他文献
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{{ truncateString('JAMES Douglas THOMAS', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 9.81万 - 项目类别:
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