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Biomaterials-based metabolic rescue of dendritic cells for vaccine design

基于生物材料的树突状细胞代谢拯救用于疫苗设计

基本信息

批准号：
10543178
负责人：
Abhinav Acharya
金额：
$ 32.28万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543178
关键词：
Adjuvant Adoptive Transfer Antigen-Presenting Cells Antigens BRAF gene Biocompatible Materials Biological Assay Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Carbon Cells Citric Acid Cycle Collecting Cell Combination immunotherapy Complex Contralateral Cytotoxic T-Lymphocytes Data Dendritic Cells Dendritic cell activation Development Dopachrome isomerase Dose Formulation Frequencies Fructose Future GATA3 gene Generations Genus Hippocampus Glutaminase Glycolysis Glycolysis Inhibition Glycolysis Pathway Goals Growth Helper-Inducer T-Lymphocyte Human Immune Immunocompetent Immunohistochemistry Immunotherapy In Vitro Intravenous Kidney Kinetics Liver Lysine Macrophage Malignant Neoplasms Malignant neoplasm of ovary Maximum Tolerated Dose Measures Metabolic Metabolic Pathway Metabolism Mission Mitochondria Modeling Mus NF-kappa B Organ Oxygen Consumption Pathway interactions Peptides Phagocytosis Poly I-C Polymers Production Proliferating Public Health Publishing Reaction Reactive Oxygen Species Research Research Project Grants Respiration Role Safety Sorting Stress Tests Succinates T cell response T memory cell T-Lymphocyte Technology Testing Toxic effect Treatment Protocols Tumor Burden Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells United States National Institutes of Health Vaccine Design Vaccine Therapy Vaccines Vertebral column Work appropriate dose cancer cell cancer type cytotoxic draining lymph node ethylene glycol exhaust experimental study extracellular in vivo inhibitor inorganic phosphate long term memory lymph nodes melanoma metabolic fitness mitochondrial fitness mouse model mutant nanoparticle neoplasm immunotherapy novel particle prevent programmed cell death protein 1 programs response scale up subcutaneous tumor tumor growth tumor microenvironment vaccine efficacy vaccine response

项目摘要

Abstract The main goal of this proposal is to develop biomaterial-based technologies that can modulate the functions of DCs and T-cells in the draining lymph nodes in the presence of systemically delivered metabolic inhibitors. The hypothesis of this proposal is that polymeric biomaterials-based particles generated from central-carbon metabolites (targeting DCs via phagocytosis) can restart glycolysis/TCA cycle in DCs in the presence of metabolic inhibitors and will also induce robust vaccine responses in immunocompetent mice. Notably, we have generated polymers of central-carbon metabolites from glycolysis and TCA cycle, which were able to activate DCs even in the presence of metabolic inhibitors. Moreover, these particles were able to rescue the metabolic inhibition, as observed by up-regulated extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in bone marrow derived DCs. In vivo PEGS particle formulations delivering TRP-2 peptide (without any adjuvant), were able to prevent the growth of subcutaneous B16F10 tumors in the presence of CB-839 a glutaminase inhibitor. Similarly, F16BP vaccine particles delivering TRP2 peptide antigen along with poly(I:C) as adjuvant and PFK15, a glycolytic inhibitor, were able to reverse the growth of subcutaneous YUMM1.1 tumors. The hypothesis of this proposal will be tested using the following specific aims: Aim 1: Evaluate if F16BP particles induce antigen-specific long-term memory T cell responses in immunocompetent mice in the presence of glycolytic inhibitor PFK15. Aim 2: Determine if PEGS particles can induce antigen-specific long-term T cell responses in immunocompetent mice in the presence of glutaminase inhibitor CB-839. Aim 3: Determine toxicity profile and maximum tolerable doses of vaccines. The results obtained from these experiments will shed light on the effect of metabolic reprogramming on the efficacy of vaccine therapy.

抽象的该提案的主要目标是开发基于生物材料的技术，可以调节在全身递送代谢抑制剂的情况下，引流淋巴结中的 DC 和 T 细胞。这该提案的假设是，由中心碳产生的基于聚合生物材料的颗粒代谢物（通过吞噬作用靶向 DC）可以在存在以下物质的情况下重新启动 DC 中的糖酵解/TCA 循环代谢抑制剂，还将在免疫功能正常的小鼠中诱导强烈的疫苗反应。值得注意的是，我们通过糖酵解和 TCA 循环生成了中心碳代谢物的聚合物，能够即使存在代谢抑制剂也能激活 DC。此外，这些粒子能够拯救通过细胞外酸化率 (ECAR) 和氧的上调观察到代谢抑制骨髓来源的 DC 的消耗率 (OCR)。体内递送 TRP-2 的 PEGS 颗粒制剂肽（不含任何佐剂）能够阻止皮下 B16F10 肿瘤的生长 CB-839（一种谷氨酰胺酶抑制剂）的存在。同样，F16BP 疫苗颗粒递送 TRP2 肽抗原与聚 (I:C) 作为佐剂和 PFK15（一种糖酵解抑制剂）能够逆转皮下YUMM1.1肿瘤。该提案的假设将使用以下具体内容进行测试目标：目标 1：评估 F16BP 颗粒是否诱导抗原特异性长期记忆 T 细胞反应糖酵解抑制剂 PFK15 存在下的免疫活性小鼠。目标 2：确定 PEGS 颗粒是否可以在谷氨酰胺酶存在的情况下，在免疫活性小鼠中诱导抗原特异性长期 T 细胞应答抑制剂CB-839。目标 3：确定疫苗的毒性特征和最大耐受剂量。结果从这些实验中获得的结果将揭示代谢重编程对功效的影响疫苗治疗。