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

摘要 对免疫检查点阻断(ICB)的抵抗力，以及在部分 反应可能通过内在机制或后天机制发生。机制细节和临床相关性 癌症是如何逃脱ICB的，目前尚不清楚。在以前的工作中，我们发现对联合ICB的抗性 放射(RT)和抗CTLA4联合治疗可在PDL1表达上调的情况下进行。这是关联的 干扰素刺激基因(ISGs)的表达增加。我们的初步数据揭示了 干扰素信号传导驱动的肿瘤内源性耐药机制及其与肿瘤的关系 负担。此外，最近的临床结果确定了肿瘤负担和ICB疗效之间的联系，揭示了 耗竭T细胞(TeX)的变化。我们在这两种肿瘤中都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PDL1非依赖的抗性机制，由 干扰素信号转导时间延长与肿瘤负担以补充平行临床试验，这些试验测试了 RT+α+CTLA4+PD1在晚期癌症患者中的应用，本项目旨在研究α非依赖性 通过检测肿瘤细胞和T细胞的耐药机制。我们将检验这样一种假设：肿瘤 负担和延长的干扰素信号导致两种细胞类型的相互基因组/表观基因组变化，限制了 RT+αCTLA4+αPDL1/PD1的有效性，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 理解干扰素，肿瘤微环境中的一个主要信号，如何矛盾地驱动额外的但 有针对性的免疫检查点途径，以控制T细胞耗竭和对联合治疗的耐药性。在……里面 这样，我们将通过关注潜在的基础来为下一代临床试验的设计提供信息 持久反应的决定因素。

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.