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 - 由癌症中的ER压力控制的免疫代谢程序肿瘤会产生敌对的微环境，从而阻碍有效抗癌的发展和维护免疫。然而，在这种危害环境中，肿瘤内免疫细胞如何整合和解释持续的应力信号仍然未完全定义。我们发现了恶性肿瘤中的不利条件破坏了浸润免疫细胞中内质网（ER）的蛋白质折叠能力，引发失调促进免疫抑制和恶性进展的“ ER应力”反应。因此，我们假设肿瘤微环境中的理解和靶向有害的ER应力反应是开发新的，更有效形式的癌症免疫疗法的主要机会。在关键最近的进步，我们确定ER1A-XBP1的ER应力反应抑制了表达 Tagln2是一种在T细胞激活和效应子功能中实现的可理解的细胞骨架蛋白。我们发现缺乏XBP1S的T细胞表现出增强的TAGLN2表达，该表达支持其保护功能肿瘤部位。此外，我们确定TAGLN2协调了主要代谢计划，以维持强大的t 细胞线粒体呼吸和效应子能力。这些新发现促使我们剖析了新型IRE1A-XBP1S-TAGLN2轴控制T细胞代谢和癌症功能的机制。因此，该项目的目标是i）理解ER压力如何抑制TAGLN2表达，ii）确定 TAGLN2用坚固的代谢适应性为T细胞配对了支持其抗肿瘤活性的稳健代谢适应性，iii）确定 TAGLN2替代疗法增强了实体瘤中嵌合抗原受体（CAR）-T细胞的活性。我们假设通过禁用TAGLN2-的肿瘤内T细胞功能，失调的ER应力反应阻碍了tagln2- 驱动的生物能程序以及维持这种细胞骨架线粒体轴可用于改进自适应T细胞免疫疗法在实体瘤中的效率。我们将在通过以下特定目的，免疫疗法 - 不良卵巢癌（OVCA）： AIM 1。定义ER应力反应抑制OVCA浸润T细胞中TAGLN2的机制。 AIM 2。确定Tagln2作为胜任抗肿瘤T细胞功能的代谢驱动力的作用。 AIM 3。检验以下假设：保存TAGLN2活性增强了OVCA中的CAR-T细胞免疫疗法。总的来说，拟议的项目将扩大我们对肿瘤免疫调节的机械理解微环境并有望为新的干预措施铺平道路，以提高细胞的效率免疫疗法对固体恶性肿瘤。