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Investigating Amino Acid Depletion in the Tumor Microenvironment as a Metabolic Immune Checkpoint

研究肿瘤微环境中的氨基酸消耗作为代谢免疫检查点

基本信息

批准号：
10534729
负责人：
CRAIG B THOMPSON
金额：
$ 40.7万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-02 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534729
关键词：
Acetylcysteine Address Affect Amino Acids Antigens Architecture CTLA4 gene Carcinoma Cell Proliferation Cell Survival Cell physiology Cells Charge Chromatin Chronic Clinical Collagen Colon Carcinoma Colorectal Cancer Consumption Cysteine Cystine DNA Methylation Data Differentiation and Growth Effector Cell Environment Epithelium Extracellular Matrix Proteins Extracellular Protein Extracellular Space Fibroblasts Functional disorder Gene Expression Glucose Glutamates Glutaminase Glutamine Glutamine-Specific tRNA Glutathione Homeostasis Human Immune Immune response Immune system Immunosuppression Immunotherapy Impairment In Vitro Infiltration Inflammatory Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolic Activation Methionine Methylation Mitochondria Non-Essential Amino Acid Nutrient Nutrient Depletion Nutritional Requirements Oxidation-Reduction Pathway interactions Patients Phenotype Productivity Proline Property Proteins Role Solid Neoplasm Source Stromal Cells Supplementation T cell response T cell therapy T-Cell Activation T-Lymphocyte Transfer RNA Aminoacylation Transforming Growth Factor beta Translations Tumor Immunity Tumor-infiltrating immune cells anti-tumor immune response cancer cell cancer infiltrating T cells cancer subtypes cell transformation cell type cytokine effector T cell exhaust exhaustion experimental study extracellular glucose uptake glutamine-tRNA histone methylation immune checkpoint immune function immunosuppressive macrophages improved in vivo malignant breast neoplasm metabolic abnormality assessment neoplastic cell novel prevent programmed cell death protein 1 restraint success therapeutically effective tumor tumor microenvironment uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Activating a patient's immune system to target cancer cells has emerged as an effective therapeutic strategy. However, many cancer subtypes, including epithelial malignancies such as pancreatic, breast, and colorectal cancers still respond poorly to existing T-cell therapies. Why immune-based strategies have shown such poor success in treating these common cancers is not known. In addition to characterizing the inhibitory checkpoints that restrain T-cell activation, our laboratory previously demonstrated that activated T-cells depend on extracellular glucose and amino acids to sustain their viability and effector function. Over the last several years, we have been studying the metabolic properties of the multiple cell types present in the tumor microenvironment. In addition to tumor cell consumption of glucose and free amino acids, we have found that tumor-associated fibroblasts can deplete glutamine and other nonessential amino acids from the extracellular space. In particular, the tumor and fibroblast-dependent depletion of glutamine and cystine (cysteine) makes it difficult for cells in the tumor microenvironment to maintain protein translation and redox homeostasis. We have uncovered multiple novel mechanisms by which tumor and stromal cells adapt to amino acid depletion, including utilizing extracellular proteins as a source of amino acids through macropinocytosis, adaptive alterations in translation, and activation of the transsulfuration pathway to maintain endogenous cysteine levels and glutathione levels. Whether tumor-infiltrating immune cells can use any or all of these adaptations is unknown. Our preliminary evidence suggest that T-cells are unable to maintain their viability and effector function when depleted of either glutamine and/or cysteine. Therefore, we hypothesize that the tumor microenvironment drives immunosuppression by depleting these non-essential amino acids. To address this hypothesis, we propose three Specific Aims: 1) Study whether cancer-associated fibroblasts contribute to immunosuppression by depleting extracellular free amino acids, 2) Determine the mechanism by which glutamine depletion impairs anti-tumor immune function, and 3) Examine whether cysteine depletion in tumor- infiltrating immune cells results in impaired mitochondrial redox homeostasis and/or reduced effector function. Through these studies, we hope to demonstrate how depletion of glutamine and cysteine drives immunosuppression within the tumor microenvironment and identify mechanisms by which these amino acids can be restored to levels that will sustain an anti-tumor immune response.

项目总结/文摘