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

• 批准号: 10322658
• 负责人: Abhinav Acharya
• 金额: $ 32.48万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322658
• 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; 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; Light; Liver; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Measures; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Mus; Organ; Oxygen Consumption; Pathway interactions; Peptides; Phagocytosis; Poly I-C; Polymers; Production; Proliferating; Public Health; Publishing; Reaction; Reactive Oxygen Species; Regulatory T-Lymphocyte; Research; Research Project Grants; Respiration; Role; Safety; Sorting - Cell Movement; 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; base; cancer cell; cancer type; cytotoxic; draining lymph node; exhaust; experimental study; extracellular; in vivo; inhibitor; long term memory; lymph nodes; macrophage; melanoma; metabolic fitness; mitochondrial fitness; mouse model; mutant; nanoparticle; neoplasm immunotherapy; novel; particle; prevent; programmed cell death protein 1; response; scale up; subcutaneous; tumor; tumor growth; tumor microenvironment; vaccine efficacy; vaccine response

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 已经从糖酵解和 TCA 循环中生成了中心碳代谢物的聚合物，这些聚合物能够 即使存在代谢抑制剂也能激活 DC。此外，这些粒子能够拯救 代谢抑制，通过细胞外酸化率 (ECAR) 和氧的上调观察到 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 目的：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。