Project 4

项目4

基本信息

批准号：
10676739
负责人：
Paulo Cesar Rodriguez
金额：
$ 32.8万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-25 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676739
关键词：
Ablation Agonist Antioxidants Beds Binding Biology Bone Marrow CD8-Positive T-Lymphocytes Cancer Patient Cell Count Cell physiology Cells Cellular Stress Clinical Cystine DNA Data Detection Development Effectiveness Endoplasmic Reticulum Event Extravasation Foundations Goals Homeostasis Immune Immunity Immunocompetent Immunotherapy Impairment In Situ Infiltration Interferon Type I Interferons Link Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator Metabolic Metabolism Mitochondria Mitochondrial DNA Modeling Monitor Mus Myeloid Cells Myeloid-derived suppressor cells Myelopoiesis Nature Pathway interactions Patients Phosphotransferases Process Production Proteins Radio Reaction Reactive Oxygen Species Reporting Role Seminal Signal Transduction Stimulator of Interferon Genes Stress T cell response T-Lymphocyte TP53 gene Testing Therapeutic Tumor Immunity Tumor-infiltrating immune cells anticancer treatment cancer immunotherapy carcinogenesis checkpoint therapy effective therapy endoplasmic reticulum stress experience immunogenic in vivo information gathering inhibitor insight lung cancer cell mitochondrial dysfunction novel strategies novel therapeutic intervention predicting response programs response success synergism tumor tumor microenvironment

项目摘要

PROJECT 4 SUMMARY: METABOLIC AND FUNCTIONAL REPROGRAMMING OF IMMUNOSUPPRESSIVE MYELOPOIESIS IN LUNG TUMORS Lung cancer cells and tumor-infiltrating immune subsets activate an integrated signaling network known as the unfolded protein response (UPR) as a reaction to the sustained and pronounced endoplasmic reticulum (ER) expansion and stress induced by the precarious conditions of the tumor microenvironment (TME). The UPR promotes cellular adaptation processes in the TME that initially drive the survival of ER stressed cells. However, the role of the intrinsic activation of UPR drivers in immune cells in the modulation of anti-tumor immunity remains unclear. Expansion of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts has emerged as a primary mechanism to block protective anti-tumor immunity and a major obstacle to the success of lung cancer immunotherapy. To date, however, the approaches to therapeutically block MDSC are limited to myelosuppressive inhibitors that are only partially effective and cause rebound in MDSC numbers as the bone marrow recovers. The primary goal of this study is to dissect the intrinsic mechanistic interplay between the sustained over-activation of UPR-related PKR-like ER kinase (PERK) and the metabolic events that polarize MDSC into highly immunoinhibitory myeloid cells in lung tumors. In cooperation with Projects #1-3, we hypothesize that the intrinsic elimination of PERK functionally and metabolically transforms MDSC into immunostimulatory cells that restore protective anti-tumor immunity. Mechanistically, we argue that the ablation of PERK impairs NRF2 signaling, which alters the expression of the cystine transporter, xCT, and promotes the accumulation of reactive oxygen species (ROS) that disrupt mitochondrial homeostasis and trigger the TP53 ↔ STING-dependent production of type I interferons. Thus, therapeutic inhibition of PERK in tumor beds will overcome MDSC-linked T cell suppression and boost the effects of several forms of immunotherapy in lung cancer. We propose the following Aims: In Aim 1, we will evaluate the role of blunted NRF2-related cystine metabolism in the mitochondrial dysfunction observed in PERK-deficient MDSC from lung tumors. In Aim 2, we will elucidate the impact of the TP53 ↔ cGAS ↔ STING axis in the functional transformation of PERK-null MDSC into myeloid cells with the ability to promote anti-tumor T cell responses. In Aim 3, we will test whether therapeutic modulation or detection of active PERK, or its down-stream targets, serve as effective strategies to enhance and monitor the activities of immunotherapy in lung cancer. The development of these Aims will have a profound impact on the field by substantiating a primary signal whereby tumors regulate myeloid cell function through activation of key ER stress mediators. This will provide a mechanistic rationale for the development of novel therapeutic approaches to effectively reprogram MDSC into myeloid cells that induce anti-tumor immunity, and to enhance the efficacy of lung cancer immunotherapy.

项目 4 摘要：代谢和功能重编程肺肿瘤中的免疫抑制性骨髓生成肺癌细胞和肿瘤浸润免疫亚群激活一个称为“信号通路”的整合信号网络未折叠蛋白反应 (UPR) 作为对持续且显着的内质网 (ER) 的反应肿瘤微环境（TME）的不稳定条件引起的扩张和应激。促进 TME 中的细胞适应过程，最初推动 ER 应激细胞的存活。免疫细胞中 UPR 驱动程序的内在激活在抗肿瘤免疫调节中的作用仍然存在骨髓源性抑制细胞（MDSC）在荷瘤宿主中的扩增已成为一种尚不清楚的现象。阻断保护性抗肿瘤免疫的主要机制和肺癌成功的主要障碍然而，迄今为止，治疗性阻断 MDSC 的方法仅限于免疫疗法。骨髓抑制抑制剂仅部分有效并导致 MDSC 数量反弹这项研究的主要目标是剖析骨髓之间的内在机械相互作用。 UPR 相关 PKR 样 ER 激酶 (PERK) 持续过度激活以及极化的代谢事件我们与项目 #1-3 合作，将 MDSC 转化为肺肿瘤中的高度免疫抑制性骨髓细胞。坚持认为 PERK 的内在消除在功能和代谢上将 MDSC 转化为从机制上讲，我们认为消融是恢复保护性抗肿瘤免疫力的免疫刺激细胞。 PERK 会损害 NRF2 信号传导，从而改变胱氨酸转运蛋白 xCT 的表达，并促进活性氧 (ROS) 的积累会破坏线粒体稳态并触发 TP53 ↔ I 型干扰素的 STING 依赖性产生因此，对肿瘤床中的 PERK 进行治疗性抑制。克服 MDSC 相关 T 细胞抑制并增强多种形式的肺部免疫疗法的效果我们提出以下目标：在目标 1 中，我们将评估 NRF2 相关胱氨酸代谢减弱在线粒体功能障碍中的作用在肺部肿瘤的 PERK 缺陷型 MDSC 中观察到。在目标 2 中，我们将阐明 TP53 ↔ cGAS ↔ STING 轴在功能转换中的影响 PERK-null MDSC 进入骨髓细胞，能够促进抗肿瘤 T 细胞反应。在目标 3 中，我们将测试活性 PERK 或其下游靶标的治疗调节或检测是否作为增强和监测肺癌免疫治疗活性的有效策略。这些目标的制定将通过证实主要信号对该领域产生深远的影响因此，肿瘤通过激活关键的内质网应激介质来调节骨髓细胞功能。开发新的治疗方法以有效地将 MDSC 重编程为的机制原理骨髓细胞可诱导抗肿瘤免疫，并增强肺癌免疫治疗的疗效。