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骨髓骨髓肺癌细胞和肿瘤浸润的免疫吸收激活一个被称为该的综合信号网络展开的蛋白质反应（UPR）是对持续且明显的内质网（ER）的反应肿瘤微环境（TME）的不稳定条件引起的膨胀和应力。 UPR 促进TME中最初驱动ER应力细胞存活的TME中的细胞适应过程。然而， UPR驱动因素在免疫细胞中的内在激活在抗肿瘤免疫的调节中的作用不清楚。肿瘤宿主中髓样衍生的抑制细胞（MDSC）的扩展已成为一种阻止保护性抗肿瘤免疫力和成功肺癌成功的主要障碍的主要机制免疫疗法。但是，迄今为止，治疗方法阻止MDSC的方法仅限于骨髓抑制剂仅部分有效并导致MDSC数量反弹作为骨骼骨髓恢复。这项研究的主要目的是剖析与UPR相关的PKR样ER激酶（PERK）和代谢事件的持续过度激活 MDSC进入肺部肿瘤中高度免疫抑制性髓样细胞。与1-3的项目合作，我们假设固有消除PERK在功能上和代谢中将MDSC转化为恢复受保护的抗肿瘤免疫组织的免疫刺激细胞。从机械上讲，我们认为消融 PERK会损害NRF2信号传导，该信号传导改变了Cystine Transporter，XCT的表达并促进反应性氧（ROS）的积累，破坏线粒体稳态并触发TP53↔ I型干扰素的sting依赖性产生。那就是肿瘤床的治疗性抑制作用克服MDSC连接的T细胞抑制并增强肺中几种形式的免疫疗法的影响癌症。我们提出以下目标：在AIM 1中，我们将评估钝化NRF2相关的Cystine代谢在线粒体功能障碍中的作用在肺部肿瘤的PERK缺陷MDSC中观察到。在AIM 2中，我们将阐明TP53 CGAS↔刺激轴对功能转换的影响将MDSC振作到髓样细胞中，具有促进抗肿瘤T细胞反应的能力。在AIM 3中，我们将测试热调制或检测活动PERK或其下游目标，即作为增强和监测肺癌免疫疗法活动的有效策略。这些目标的发展将通过证实主要信号对现场产生深远的影响肿瘤通过激活关键的ER应力介质调节髓样细胞功能。这将提供一个开发新疗法方法以有效将MDSC重新编程为影响抗肿瘤免疫崇拜的髓样细胞，并提高肺癌免疫疗法的效率。