Immunoengineering cellobiose as a fuel source for T cells

免疫工程纤维二糖作为 T 细胞的燃料来源

基本信息

批准号：
10539922
负责人：
MANISH J BUTTE
金额：
$ 19.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539922
关键词：
Adoptive Cell Transfers Anabolism Bioenergetics Cancer Model Carbon Catabolic Process Cell Line Cell physiology Cells Cellular Metabolic Process Cellulose Clinical Consumption Cytosol Data Disaccharides Dose Drug Kinetics Energy-Generating Resources Engineering Environment Enzymes Epitopes GH1 gene Gene Proteins Genes Glucans Glucose Glycoside Hydrolases Glycosides Goals Head Immune Immunologist Impairment Individual Infection Infusion procedures Intermittent fasting Journals Light Lymphoma Malignant Neoplasms Mammalian Cell Medicine Metabolic Metabolic Pathway Metabolism Microbe Monosaccharides Mus Nature Neurospora Pathway interactions Patients Plants Play Production Proliferating Protein Engineering Proteins Publishing Pyruvate Role Solid Neoplasm Source System T-Lymphocyte Testing Toxicity Tests Transgenic Mice Transgenic Organisms Translating Tumor-Infiltrating Lymphocytes cancer cell cancer immunotherapy cancer therapy chimeric antigen receptor T cells cytokine cytotoxicity deprivation effector T cell engineered T cells experimental study fighting fungus immunoengineering immunogenicity improved innovation melanoma metabolomics neoplastic cell sugar translation to humans tumor tumor growth tumor metabolism tumor progression

项目摘要

Abstract Glucose levels are low in the microenvironment of solid tumors due to the voracious nature of tumor metabolism, impeding the function of tumor-infiltrating T cells that might otherwise control tumor growth. T cells require glucose for energetics, cytokine production, proliferation, and cytotoxicity. Infusing additional glucose into patients is not a viable solution as it would feed only the tumor and further starve T cells. Adoptive cell therapies (CAR-T cells) often fail in solid tumors because of this metabolic hurdle created by tumors. Cellobiose, a polymer of glucose found abundantly in plant matter in the form of cellulose, has the potential to serve as a carbon and energy source. However, mammalian cells cannot catabolize cellobiose. Our preliminary data show that engineering two proteins into T cells allows them to make use of cellobiose. Thus, we already have a working system set up to engineer T cells to have an exclusive source of glucose to fight tumors. We showed this glucose source is completely inaccessible to tumors. Our long-term goal is to translate this capability to T cells that are engineered for cancer immunotherapy (e.g., CAR-T cells). Our team includes T-cell immunologists at UCLA assisted by expert colleagues in immune metabolism and cancer immunotherapies. In this R21 proposal, we will in Aim 1, characterize as cellobiose is hydrolyzed to glucose, and trace its carbons into various metabolic and biosynthetic pathways and provide energy. We test the capacity of cells to use cellobiose-derived glucose through state-of-the-art metabolomics in 293 cell lines and primary T cells. In Aim 2, we test toxicity and pharmacokinetics to prepare for melanoma experiments in mice. We test in a proof-of-concept experiment the ability of T cells to fight mouse melanomas, using transduced pmel TCR transgenics and CAR-T cells that target melanoma. By adding cellobiose metabolism to engineered T cells, we offer a new fuel source and a synergistic approach that significantly potentiates cancer immunotherapies.

抽象的由于肿瘤的贪婪性质，实体瘤的微环境中的葡萄糖水平很低代谢，阻碍了可能控制肿瘤生长的肿瘤浸润T细胞的功能。 t 细胞需要葡萄糖才能进行能量，细胞因子产生，增殖和细胞毒性。注入其他葡萄糖进入患者不是可行的溶液，因为它只会喂养肿瘤并进一步饥饿的T细胞。收养由于肿瘤产生的这种代谢障碍，细胞疗法（CAR-T细胞）通常在实体瘤中失败。纤维二糖是一种以纤维素形式发现的葡萄糖聚合物，具有潜力用作碳和能源。然而，哺乳动物细胞不能分解纤维酶。我们的初步数据表明，将两种蛋白质的工程纳入T细胞，使它们可以利用纤维二糖。因此，我们已经有一个工作系统设置为工程师T细胞，具有与肿瘤作斗争的独家葡萄糖来源。我们展示了该葡萄糖源完全无法访问肿瘤。我们的长期目标是将这种能力转化为针对癌症免疫疗法设计的T细胞（例如，CAR-T细胞）。我们的团队包括加州大学洛杉矶分校的T细胞免疫学家，由免疫专业同事协助代谢和癌症免疫疗法。在此R21提案中，我们将在AIM 1中，特征为核二聚体水解为葡萄糖，并将其碳追踪到各种代谢和生物合成途径中，并提供活力。我们测试细胞通过最先进的代谢组学中使用纤维酶衍生的葡萄糖的能力 293个细胞系和原代T细胞。在AIM 2中，我们测试毒性和药代动力学为黑色素瘤做准备小鼠的实验。我们在概念验证实验中测试T细胞对抗小鼠黑色素瘤的能力，使用靶向黑色素瘤的转导PMEL TCR转基因和CAR-T细胞。通过在工程的T细胞中添加纤维二糖代谢，我们提供了一种新的燃料来源和协同方法这显着增强了癌症免疫疗法。