Stress Pathways in Tumors Drive Global MDSC Activity and Survival through Chop

肿瘤中的应激途径通过 Chop 驱动全球 MDSC 活动和生存

• 批准号: 9172081
• 负责人: Paulo Cesar Rodriguez
• 金额: $ 25.27万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172081
• 关键词: Amino Acids; Animals; Antigens; Apoptosis; Arginine; Biological Response Modifiers; Biology; Bone Marrow; CCAAT-Enhancer-Binding Proteins; CD8B1 gene; Cell physiology; Chimera organism; Colon Carcinoma; Cysteine; Data; Development; Dinoprostone; Encapsulated; Functional disorder; Genetic; Goals; Health; Homeostasis; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Immunotherapy; Individual; Injection of therapeutic agent; Knockout Mice; Link; Liposomes; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Methodology; Mus; Myelogenous; Myeloproliferative disease; Natural Killer Cells; Pathway interactions; Patients; Peroxonitrite; Phosphorylation; Protein Isoforms; Proteins; Public Health; Reactive Oxygen Species; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Small Interfering RNA; Stress; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Translating; Treatment Efficacy; Tumor Immunity; Up-Regulation; Work; anergy; antitumor effect; base; biological adaptation to stress; cancer cell; design; in vivo; innovation; insight; neoplasm immunotherapy; neoplastic cell; novel; novel therapeutic intervention; prevent; response; sensor; tumor; tumor growth

DESCRIPTION (provided by applicant): Accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is an important mechanism of suppression of T and NK cell responses and a major obstacle to immunotherapy. MDSC inhibitory activity has been attributed to several pathways, including the depletion of the amino acids arginine and cysteine; the release of reactive oxygen species, peroxynitrites, and prostaglandin E2; and the induction of regulatory T cells. Unfortunately, the understanding of the immune-inhibitory mechanisms induced by MDSC has not yet been translated into successful therapies to globally block MDSC function in cancer. We postulate that the identification and inhibition of the central mediators of MDSC-immune regulatory activity in tumors will overcome T cell suppression and increase the efficacy of T cell-based immunotherapies. In this proposal, we aim to determine the role of the C/EBP homologous stress-related protein (Chop), a common stress sensor usually associated with the induction of cellular apoptosis, as a master regulator of the immune suppressive activity of MDSC. We hypothesize that the induction of Chop in MDSC by multiple stress-related factors, globally drives the ability of MDSC to inhibit T cell responses and modulates MDSC turnover/survival homeostasis. Therefore, therapeutic inhibition of Chop or its upstream mediators in tumors will block MDSC function, restore protective anti-tumor effector T cell responses, and increase the efficacy of T cell-based immunotherapies. This hypothesis is based upon our extensive preliminary findings suggesting the central role of Chop on MDSC activity. We will test our hypothesis and achieve the objectives of this study through the following Specific Aims: (1) To determine the mechanisms by which the expression of Chop in the stroma regulates the immune suppression activity and the accumulation of MDSC in tumors. (2) To determine the mechanisms that induce Chop expression in tumor-infiltrating MDSC. (3) To test the prediction that pharmacological inhibition or genetic deletion of Chop will block MDSC function and increase the efficacy of T cell-based immunotherapies in cancer. Completion of the proposed study will describe for the first time how multiple stress factors in tumors drive global MDSC activity through a unique pathway. In addition, the results will help characterize and develop a novel therapeutic approach, which carries the potential to block the global immune inhibitory functions of MDSC and to restore protective T cell immunity in cancer. Moreover, the methodology established in this proposal could be applied into other diseases where MDSC are major mediators of T cell suppression.

描述（由申请方提供）：骨髓源性抑制细胞（MDSC）在荷瘤宿主中的蓄积是抑制T和NK细胞应答的重要机制，也是免疫治疗的主要障碍。MDSC抑制活性归因于几种途径，包括氨基酸精氨酸和半胱氨酸的消耗;活性氧、过氧亚硝酸盐和前列腺素E2的释放;以及调节性T细胞的诱导。不幸的是，对MDSC诱导的免疫抑制机制的理解尚未转化为成功的治疗方法，以全面阻断MDSC在癌症中的功能。我们假设，识别和抑制中枢介质， 肿瘤中的MDSC免疫调节活性将克服T细胞抑制并增加基于T细胞的免疫疗法的功效。在这个提议中，我们的目标是确定C/EBP同源应激相关蛋白（Chop）的作用，这是一种常见的应激传感器，通常与诱导细胞凋亡相关，是MDSC免疫抑制活性的主要调节因子。我们假设，多种应激相关因素诱导MDSC中的Chop，在全球范围内驱动MDSC抑制T细胞应答的能力，并调节MDSC周转/存活稳态。因此，肿瘤中Chop或其上游介质的治疗性抑制将阻断MDSC功能，恢复保护性抗肿瘤效应T细胞应答，并增加基于T细胞的免疫疗法的功效。这一假设是基于我们广泛的初步研究结果，表明Chop对MDSC活性的核心作用。我们将通过以下具体目的来验证我们的假设并实现本研究的目的：（1）确定Chop在基质中的表达调节免疫抑制活性和MDSC在肿瘤中积聚的机制。(2)确定诱导肿瘤浸润MDSC中Chop表达的机制。(3)检测Chop的药理学抑制或基因缺失将阻断MDSC功能并增加基于T细胞的免疫疗法在癌症中的疗效的预测。这项研究的完成将首次描述肿瘤中的多种应激因素如何通过独特的途径驱动全球MDSC活性。此外，这些结果将有助于表征和开发一种新的治疗方法，这种方法有可能阻断MDSC的整体免疫抑制功能，并恢复癌症中的保护性T细胞免疫。此外，该建议中建立的方法可以应用于MDSC是T细胞抑制的主要介质的其他疾病。