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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.

摘要