Biomaterials-based metabolic rescue of dendritic cells for vaccine design

摘要 这项提议的主要目标是开发基于生物材料的技术，这种技术可以调节 在系统递送代谢抑制剂存在的情况下，引流淋巴结中的DC和T细胞。这个 这一提议的假设是，基于生物材料的聚合物颗粒产生于中心碳 代谢产物(通过吞噬作用靶向DC)可以在存在的情况下重新启动DC的糖酵解/TCA循环 新陈代谢抑制剂，还将在具有免疫能力的小鼠中诱导强大的疫苗反应。值得注意的是，我们 在糖酵解和TCA循环中产生了中心碳代谢产物的聚合物，这些聚合物能够 即使在代谢抑制剂存在的情况下也能激活DC。此外，这些粒子能够拯救 代谢抑制，通过上调胞外酸化率(ECAR)和氧气观察到 骨髓来源DC的消耗率(OCR)。提供色氨酸-2的体内聚乙二醇胺颗粒制剂 多肽(不含任何佐剂)能阻止B16F10皮下肿瘤的生长 谷氨酰胺酶抑制剂CB-839的存在。同样，F16BP疫苗颗粒传递Trp2肽 抗原、聚(I：C)作为佐剂和糖酵解抑制剂PFK15能够逆转细胞的生长。 YUMM1.1皮下肿瘤。这项提议的假设将使用以下具体情况进行测试 目的：目的1：评价F16BP颗粒能否诱导小鼠体内抗原特异性的长期记忆T细胞反应 在存在糖酵解抑制剂PFK15的情况下具有免疫活性的小鼠。目标2：确定pegs粒子是否可以 谷氨酰胺酶诱导免疫活性小鼠产生抗原特异性长期T细胞反应 缓蚀剂CB-839。目的3：确定疫苗的毒性分布和最大耐受量。结果是 从这些实验中获得的结果将有助于阐明代谢重新编程对药物疗效的影响 疫苗疗法。

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.