Immunometabolic Programs Controlled by ER Stress in Cancer

癌症中内质网应激控制的免疫代谢程序

基本信息

批准号：
10713279
负责人：
Juan R Cubillos-Ruiz
金额：
$ 58.96万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713279
关键词：
ATF6 gene Ascites Bioenergetics Biological Assay CD8-Positive T-Lymphocytes Cancer Control Cancer Patient Cell physiology Cells Cellular Metabolic Process Cellular immunotherapy Chromatin Cytoskeletal Proteins Cytoskeleton Defect Development Effectiveness Elements Endocrine Endoplasmic Reticulum Epithelium Event Exhibits Exposure to Follicle Stimulating Hormone Receptor Generations Goals Homeostasis Human Immune Immune Evasion Immune system Immunosuppression Immunotherapy Intervention Knowledge Lipids Luciferases Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Maps Memory Metabolic Mitochondria Modification Molecular Organelles Pathologic Pathway interactions Process Program Sustainability Protein Biosynthesis Recurrent Malignant Neoplasm Refractory Replacement Therapy Reporter Repression Research Respiration Role SM 22 muscle protein Safety Signal Transduction Site Solid Solid Neoplasm Stress T cell infiltration T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Transcription Repressor Transgenic Mice Tumor Immunity Tumor-infiltrating immune cells XBP1 gene anti-cancer anti-tumor immune response anticancer activity arm biological adaptation to stress cancer cell cancer immunotherapy cancer infiltrating T cells cancer recurrence carcinogenesis chimeric antigen receptor T cells cytotoxic effector T cell endoplasmic reticulum stress fatty acid oxidation fatty acid-binding proteins immune cell infiltrate immunoregulation improved inhibitor metabolic fitness misfolded protein novel novel strategies ovarian neoplasm overexpression pharmacologic preservation programs protein folding sensor trafficking tumor tumor growth tumor microenvironment tumor progression uptake

项目摘要

Project Summary – Immunometabolic Programs Controlled by ER Stress in Cancer Tumors create hostile microenvironments that impede the development and maintenance of effective anti-cancer immunity. Yet, how intratumoral immune cells integrate and interpret persistent stress signals in this harsh milieu remains incompletely defined. We have uncovered that adverse conditions within malignant masses disrupt the protein-folding capacity of the endoplasmic reticulum (ER) in infiltrating immune cells, triggering dysregulated “ER stress” responses that promote immunosuppression and malignant progression. Therefore, we postulate that understanding and targeting detrimental ER stress responses in the tumor microenvironment represents a major opportunity to develop new and more effective forms of cancer immunotherapy. In a key recent advance, we determined that the IRE1a-XBP1s arm of the ER stress response inhibits the expression of Tagln2, an understudied cytoskeletal protein implicated in T cell activation and effector function. We found that XBP1s-deficient T cells demonstrate enhanced Tagln2 expression that supports their protective function at tumor sites. Moreover, we established that Tagln2 coordinates major metabolic programs that sustain robust T cell mitochondrial respiration and effector capacity. These new findings have prompted us to dissect the mechanisms by which the novel IRE1a-XBP1s-Tagln2 axis controls T cell metabolism and function in cancer. Hence, the goals of this project are to i) understand how ER stress inhibits Tagln2 expression, ii) establish that Tagln2 equips T cells with robust metabolic fitness that supports their anti-tumor activity, and iii) determine that Tagln2 replacement therapy enhances the activity of chimeric antigen receptor (CAR)-T cells in solid tumors. We hypothesize that dysregulated ER stress responses hinder intratumoral T cell function by disabling Tagln2- driven bioenergetic programs, and that sustaining this cytoskeletal-mitochondrial axis could be used to improve the efficacy of adoptive T cell immunotherapy in solid tumors. We will test this novel hypothesis in the setting of immunotherapy-refractory ovarian cancer (OvCa) through the following Specific Aims: Aim 1. Define the mechanisms by which ER stress responses inhibit Tagln2 in OvCa-infiltrating T cells. Aim 2. Establish the role of Tagln2 as a metabolic driver of competent anti-tumor T cell function. Aim 3. Test the hypothesis that preserving Tagln2 activity enhances CAR-T cell immunotherapy in OvCa. Collectively, the proposed project will expand our mechanistic understanding of immune regulation in the tumor microenvironment and promises to pave the way for novel interventions that augment the efficacy of cellular immunotherapy against solid malignancies.

项目摘要 – 癌症中内质网应激控制的免疫代谢程序肿瘤会产生不利的微环境，阻碍有效抗癌药物的开发和维持然而，肿瘤内免疫细胞如何在这种恶劣的环境中整合和解释持续的压力信号。我们发现恶性肿块内的不利条件仍不完全确定。内质网（ER）在浸润免疫细胞中的蛋白质折叠能力，引发失调 “内质网应激”反应会促进免疫抑制和恶性进展。了解并针对肿瘤微环境中的应激 ER 应激反应代表了开发新的、更有效的癌症免疫疗法的重大机会。最近的关键进展，我们确定 ER 应激反应的 IRE1a-XBP1s 臂抑制表达 Tagln2 是一种正在研究的细胞骨架蛋白，与 T 细胞激活和效应功能有关。 XBP1s 缺陷型 T 细胞表现出增强的 Tagln2 表达，支持其保护功能此外，我们确定 Tagln2 协调维持强大 T 的主要代谢程序。这些新发现促使我们剖析细胞线粒体呼吸和效应器能力。新型 IRE1a-XBP1s-Tagln2 轴控制癌症中 T 细胞代谢和功能的机制。因此，该项目的目标是 i) 了解 ER 应激如何抑制 Tagln2 表达，ii) 确定 Tagln2 使 T 细胞具有强大的代谢适应性，支持其抗肿瘤活性，并且 iii) 确定 Tagln2 替代疗法可增强实体瘤中嵌合抗原受体 (CAR)-T 细胞的活性。我们通过禁用 Tagln2- 来追踪失调的 ER 应激反应，从而阻碍瘤内 T 细胞功能。驱动的生物能计划，并且维持这种细胞骨架线粒体轴可用于改善我们将在以下背景下测试这一新假设：过继性 T 细胞免疫疗法对实体瘤的疗效。通过以下具体目标来治疗难治性卵巢癌（OvCa）：目标 1. 明确 ER 应激反应抑制 OvCa 浸润 T 细胞中 Tagln2 的机制。目标 2. 确定 Tagln2 作为抗肿瘤 T 细胞功能的代谢驱动因素的作用。目标 3. 测试保留 Tagln2 活性可增强 OvCa 中 CAR-T 细胞免疫治疗的假设。总的来说，拟议的项目将扩大我们对肿瘤免疫调节机制的理解微环境，并有望为增强细胞功效的新型干预措施铺平道路针对实体恶性肿瘤的免疫疗法。