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

• 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
• 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

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以靶向癌细胞已成为一种有效的治疗策略。 然而，许多癌症亚型，包括上皮性恶性肿瘤，如胰腺癌、乳腺癌和结直肠癌 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现得如此糟糕 治疗这些常见癌症的成功与否尚不清楚。除了表征抑制性检查点 这抑制了T细胞的激活，我们的实验室以前证明激活的T细胞依赖于 胞外葡萄糖和氨基酸维持其活性和效应器功能。在过去几年里， 我们一直在研究肿瘤中存在的多种细胞类型的代谢特性 微环境。除了肿瘤细胞消耗葡萄糖和游离氨基酸外，我们还发现 肿瘤相关成纤维细胞可以从细胞外耗尽谷氨酰胺和其他非必需氨基酸 太空。特别是，肿瘤和成纤维细胞依赖的谷氨酰胺和半胱氨酸(半胱氨酸)的耗竭使其 肿瘤微环境中的细胞难以维持蛋白质翻译和氧化还原动态平衡。我们 发现了肿瘤和间质细胞适应氨基酸耗竭的多种新机制， 包括通过巨噬细胞吞噬利用胞外蛋白质作为氨基酸的来源，适应性 翻译的改变和跨硫途径的激活以维持内源性半胱氨酸水平 和谷胱甘肽水平。肿瘤浸润性免疫细胞是否可以使用任何或所有这些适应 未知。我们的初步证据表明，T细胞无法维持其活性和效应性。 当谷氨酰胺和/或半胱氨酸被耗尽时，它就会发挥作用。因此，我们假设肿瘤 微环境通过消耗这些非必需氨基酸来驱动免疫抑制。要解决这个问题 假设，我们提出了三个具体目标：1)研究癌症相关成纤维细胞是否有助于 通过耗尽细胞外游离氨基酸来抑制免疫，2)决定了 谷氨酰胺耗竭损害抗肿瘤免疫功能，以及3)检查肿瘤中的半胱氨酸耗竭是否- 免疫细胞的渗入导致线粒体氧化还原动态平衡受损和/或效应器功能降低。 通过这些研究，我们希望证明谷氨酰胺和半胱氨酸的枯竭是如何驱动 肿瘤微环境中的免疫抑制作用及这些氨基酸的作用机制 可以恢复到维持抗肿瘤免疫反应的水平。