Project 4

项目4

• 批准号: 10438716
• 负责人: Paulo Cesar Rodriguez
• 金额: $ 33.31万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 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/10438716
• 关键词: Ablation; Agonist; Antioxidants; Beds; 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; Interferon Type I; Interferons; Link; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; 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; base; cancer immunotherapy; checkpoint therapy; effective therapy; endoplasmic reticulum stress; experience; immunogenic; in vivo; inhibitor; insight; lung cancer cell; mitochondrial dysfunction; novel strategies; novel therapeutic intervention; predicting response; response; success; tumor; tumor microenvironment

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总结： 肺肿瘤的免疫抑制性骨髓增生 肺癌细胞和肿瘤浸润性免疫亚群激活了一个整合的信号网络，称为 未折叠蛋白反应（UPR）作为对持续和明显的内质网（ER）的反应 肿瘤微环境（TME）的不稳定条件引起的扩张和应力。普遍定期审议 促进TME中最初驱动ER应激细胞存活的细胞适应过程。然而，在这方面， 免疫细胞中UPR驱动因子的内在激活在抗肿瘤免疫调节中的作用仍然存在 不清楚骨髓源性抑制细胞（MDSC）在荷瘤宿主中的扩增已经成为一种新的治疗方法。 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 免疫疗法。然而，迄今为止，治疗性阻断MDSC的方法仅限于 骨髓抑制抑制剂仅部分有效，并导致MDSC数量反弹， 骨髓恢复。本研究的主要目标是剖析内在机制之间的相互作用， UPR相关的PKR样ER激酶（PERK）的持续过度激活和代谢事件， MDSC转化为肺肿瘤中的高度免疫抑制性髓样细胞。与项目#1-3合作，我们 假设PERK的内在消除在功能上和代谢上将MDSC转化为 免疫刺激细胞恢复保护性抗肿瘤免疫。从机制上讲，我们认为消融 PERK的表达会损害NRF 2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，破坏线粒体内稳态并触发TP 53参与 STING依赖的I型干扰素的产生。因此，肿瘤床中PERK的治疗性抑制将 克服MDSC连锁的T细胞抑制并增强几种形式的免疫疗法在肺中的作用 癌我们提出以下目标： 在目的1中，我们将评估钝化的NRF 2相关胱氨酸代谢在线粒体功能障碍中的作用。 在来自肺肿瘤的PERK缺陷型MDSC中观察到。 在目标2中，我们将阐明TP 53 ParticcGAS ParticistING轴在细胞功能转化中的影响。 PERK无效MDSC进入骨髓细胞，具有促进抗肿瘤T细胞应答的能力。 在目标3中，我们将测试是否治疗调制或检测活性PERK，或其下游靶点， 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具体化一个主要信号， 由此肿瘤通过激活关键的ER应激介质来调节髓样细胞功能。这将提供一个 开发新的治疗方法以有效地将MDSC重编程为 诱导抗肿瘤免疫的骨髓细胞，并增强肺癌免疫治疗的功效。