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：
10311105
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 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10311105
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 Epithelial 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 Inflammatory Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolic Activation Methionine Methylation Mitochondria Non-Essential Amino Acid Nutrient Oxidation-Reduction Pathway interactions Patients Phenotype 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 base cancer cell 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 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.

项目摘要/摘要激活患者的免疫系统靶向癌细胞已成为一种有效的治疗策略。但是，许多癌症亚型，包括上皮性恶性肿瘤，例如胰腺，乳房和大肠癌癌症对现有的T细胞疗法的反应仍然很差。为什么基于免疫的策略表明如此糟糕未知治疗这些常见癌症的成功。除了表征抑制性检查点限制了T细胞激活，我们的实验室先前证明了激活的T细胞依赖细胞外葡萄糖和氨基酸以维持其生存力和效应功能。在过去的几年中，我们一直在研究肿瘤中存在多种细胞类型的代谢特性微环境。除了葡萄糖和游离氨基酸的肿瘤细胞消耗外，我们还发现肿瘤相关的成纤维细胞可从细胞外耗尽谷氨酰胺和其他非必需氨基酸空间。特别是，谷氨酰胺和胱氨酸（半胱氨酸）的肿瘤和成纤维细胞依赖性耗竭使得肿瘤微环境中的细胞很难维持蛋白质翻译和氧化还原稳态。我们已经发现了多种新型机制，肿瘤和基质细胞适应氨基酸的耗竭，包括利用细胞外蛋白作为氨基酸的来源翻译的改变以及维持内源性半胱氨酸水平的转化途径的激活和谷胱甘肽水平。肿瘤浸润的免疫细胞是否可以使用这些适应性的任何或全部是未知。我们的初步证据表明，T细胞无法维持其生存能力和效应器耗尽谷氨酰胺和/或半胱氨酸时的功能。因此，我们假设肿瘤微环境通过耗尽这些非必需氨基酸来驱动免疫抑制。解决这个问题假设，我们提出了三个具体目的：1）研究与癌症相关的成纤维细胞是否有助于通过耗尽细胞外氨基酸来免疫抑制，2）确定其机制谷氨酰胺耗竭会损害抗肿瘤免疫功能，3）检查肿瘤中的半胱氨酸耗竭是否浸润的免疫细胞导致线粒体氧化还原稳态和/或效应子功能降低。通过这些研究，我们希望证明谷氨酰胺和半胱氨酸驱动的耗竭肿瘤微环境内的免疫抑制并确定这些氨基酸的机制可以恢复到可以维持抗肿瘤免疫反应的水平。