Project 3: Genetic and epigenetic basis of resistance to RT and ICB

项目3：RT和ICB抗性的遗传和表观遗传基础

• 批准号: 10005192
• 负责人: E. John Wherry
• 金额: $ 53.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005192
• 关键词: Advanced Malignant Neoplasm; Antigen Presentation; Antiviral Agents; Automobile Driving; CD8-Positive T-Lymphocytes; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Data; Defect; Epigenetic Process; Event; Failure; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Human; Immune; Immune Targeting; Immune response; Immunity; Immunotherapy; Interferon-alpha; Interferons; Knock-out; Lead; Link; Malignant Neoplasms; Mus; Pathway interactions; Patients; Preclinical Testing; Radiation; Randomized Clinical Trials; Resistance; Role; STAT1 gene; Signal Transduction; T-Lymphocyte; Testing; Tumor Burden; Tumor Escape; Tumor Immunity; Up-Regulation; Work; anti-CTLA4; anti-PD-1; anti-PD-L1; base; cancer therapy; cell type; conditional knockout; cytokine; design; epigenome; epigenomics; exhaust; exhaustion; high dimensionality; immune checkpoint; immune checkpoint blockade; improved; in vivo; neoplastic cell; next generation; overexpression; partial response; pre-clinical; preclinical efficacy; programmed cell death ligand 1; programmed cell death protein 1; programs; radiation response; receptor expression; resistance mechanism; response; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment

SUMMARY Resistance to Immune Checkpoint Blockade (ICB) and failure to develop durable immunity after partial responses may occur through intrinsic or acquired mechanisms. Mechanistic details and clinical correlates on how cancer escapes ICB are lacking. In previous work, we discovered that resistance to combination ICB therapy consisting of radiation (RT) and anti-CTLA4 can occur with upregulation of PDL1. This is associated with increased expression of interferon-stimulated genes (ISGs). Our preliminary data reveal a key role for tumor-intrinsic resistance mechanisms driven by prolonged interferon (IFN) signaling and related to tumor burden. Moreover, recent clinical results define a link between tumor burden and efficacy of ICB revealed by changes in exhausted T cells (TEX). We have found critical transcriptional and epigenetic events in both tumor cells and responding TEX that may reveal PDL1-independent mechanisms of resistance that are driven by prolonged IFN signaling and tumor burden. To complement parallel clinical trials that test the combination of RT + αCTLA4 + αPD1 in patients with advanced cancer, this project seeks to investigate PDL1-independent resistance mechanisms by examining both tumor cells and T cells. We will test the hypothesis that tumor burden and prolonged IFN signaling lead to reciprocal genomic/epigenomic changes in both cell types that limit the efficacy of RT + αCTLA4 + αPDL1/PD1, and that the reversibility of these genomic/epigenomic changes impacts the efficacy and durability of responses. By integrating pre-clinical and clinical efforts, our goal is to understand how IFN, a major signal in the tumor microenvironment, can paradoxically drive additional but targetable immune checkpoint pathways to control T cell exhaustion and resistance to combination therapy. In so doing, we will inform the design of the next generation of clinical trials by focusing on underlying determinants of durable response.

总结 对免疫检查点阻断（ICB）的抵抗力和部分免疫后未能产生持久免疫力 反应可以通过内在或获得的机制发生。机械细节和临床相关性 癌症是如何逃脱ICB的在以前的工作中，我们发现对ICB组合的抗性 由放射（RT）和抗-CTLA 4组成的治疗可以伴随PDL 1的上调而发生。这与 干扰素刺激基因（ISG）的表达增加。我们的初步数据显示， 由延长的干扰素（IFN）信号传导驱动的与肿瘤相关的肿瘤内在抗性机制 负担此外，最近的临床结果确定了肿瘤负荷与ICB疗效之间的联系， 耗尽的T细胞（TEX）的变化。我们已经在两种肿瘤中发现了关键的转录和表观遗传事件 细胞和响应TEX可能揭示PDL 1独立的耐药机制， 延长的IFN信号传导和肿瘤负荷。为了补充平行临床试验， RT + α CTLA 4 + α PD 1治疗晚期癌症患者，该项目旨在研究PDL 1非依赖性 通过检查肿瘤细胞和T细胞的耐药机制。我们将检验肿瘤 负荷和延长的IFN信号传导导致两种细胞类型中的相互基因组/表观基因组变化， RT + α CTLA 4 + α PDL 1/PD 1的疗效，以及这些基因组/表观基因组变化的可逆性 影响反应的有效性和持久性。通过整合临床前和临床工作，我们的目标是 了解干扰素，肿瘤微环境中的主要信号，如何矛盾地驱动额外的，但 靶向免疫检查点途径来控制T细胞耗竭和对组合疗法的抗性。在 这样做，我们将通过关注基础研究，为下一代临床试验的设计提供信息。 持久反应的决定因素。