Project 4

项目4摘要：新陈代谢和功能重新编排 肺肿瘤的免疫抑制性骨髓生成 肺癌细胞和肿瘤浸润性免疫亚群激活一个被称为 未折叠蛋白反应(UPR)是对持续而明显的内质网(ER)的反应 由不稳定的肿瘤微环境(TME)条件引起的扩张和应力。普遍定期审议 促进TME中的细胞适应过程，最初推动内质网应激细胞的生存。然而， 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。髓系来源的抑制细胞(MDSC)在荷瘤宿主中的扩增已成为一种 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，到目前为止，治疗阻断MDSC的方法仅限于 骨髓抑制药仅部分有效，并导致骨髓间充质干细胞数量反弹 骨髓恢复了。这项研究的主要目的是剖析人与人之间的内在机制相互作用 UPR相关的PKR样ER激酶(PERK)持续过度激活及其导致极化的代谢事件 MDSC在肺肿瘤中转化为高度免疫抑制的髓系细胞。与1-3号项目合作，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，恢复保护性的抗肿瘤免疫。从机制上讲，我们认为消融 PERK损伤NRF2信号，从而改变半胱氨酸转运体XCT的表达，并促进 破坏线粒体动态平衡并触发Tp53↔的活性氧物种(ROS)积累 依赖刺痛的I型干扰素的产生。因此，治疗性地抑制肿瘤病床中的PERK将 克服MDSC相关的T细胞抑制并提高几种免疫疗法在肺内的效果 癌症。我们提出以下目标： 在目标1中，我们将评估钝化的nrf2相关半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缺乏的MDSC中观察到。 在目标2中，我们将阐明TP53↔cGAS↔刺轴在细胞功能转化中的作用。 PERK-Null MDSC转化为髓系细胞具有促进抗肿瘤T细胞反应的能力。 在目标3中，我们将测试治疗调节或活性PERK或其下游靶点的检测， 作为加强和监测肺癌免疫治疗活动的有效策略。 这些目标的发展将通过证实一个主要信号而对该领域产生深远影响 肿瘤通过激活关键的内质网应激介质来调节髓系细胞的功能。这将提供一个 开发新的治疗方法以有效地将MDSC重新编程为 髓系细胞可诱导抗肿瘤免疫，增强肺癌免疫治疗的疗效。

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.