Arginine Availability, Modulated by MDSC, Regulates T Cell Function in Cancer

由 MDSC 调节的精氨酸可用性可调节癌症中的 T 细胞功能

• 批准号: 8006436
• 负责人: AUGUSTO C. OCHOA
• 金额: $ 24.24万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006436
• 关键词: Arginine; Basic Amino Acid Transport Systems; CD3 Antigens; Cancer Patient; Cancer Vaccines; Cell Cycle Arrest; Cell physiology; Data; Environment; Gene Expression; Gene Proteins; Genes; Half-Life; Health; IL2 gene; Immunotherapy; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; Myelogenous; Nutrient; Pathway interactions; Patients; Phosphotransferases; Production; Protein Biosynthesis; Research; Resistance; Serum; Starvation; Suppressor-Effector T-Lymphocytes; T cell anergy; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Work; arginase; cyclin D2; cyclin D3; cytokine; cytotoxicity; design; inhibitor/antagonist; insight; novel strategies; novel therapeutic intervention; prevent; research study; response; reverse tolerance; therapy design; tumor

DESCRIPTION (provided by applicant): Myeloid-Derived Suppressor Cells (MDSC) expressing Arginase (ARG) 1 are potent inhibitors of T cell function in cancer. MDSC deplete L-Arginine (L-Arg) in serum and the tumor microenvironment, severely impairing anti- tumor responses. Work done in the preceding five years identified the mechanisms by which MDSC deplete L- Arg and has started to identify the molecular mechanisms by which L-Arg depletion causes T cell anergy. We found that MDSC expressing ARG 1 infiltrate tumors and deplete L-Arg by rapid incorporation through CAT transporters. This L-Arg-depleted environment causes a T cell cycle arrest by inhibiting cyclin D3 and cdk4 (but not cyclin D2 or cdk6), inhibits the production of IFNg (but not IL2), and blocks the expression of the T cell receptor z chain (CD3z), severely impairing T cell function. Inhibition of ARG 1 re-establishes proliferation, IFNg production, and CD3z expression, and triggers an anti-tumor response. These mechanisms were found in mice and patients with cancer. Our results therefore suggest that L-Arg depletion triggers the selective inhibition of specific genes important for effector functions of T cells, and not a generalized decrease in protein synthesis from nutrient starvation. The data also suggest that this phenomenon is caused by the activation of a checkpoint that mediates the inhibition of these effector mechanisms. Therefore, blocking this checkpoint may make T cells resistant to the anergizing/tolerizing effect of MDSC. The proposed research will identify the molecular mechanisms triggered by L-Arg depletion that inhibit the expression of genes and proteins necessary for T cell effector functions. We will demonstrate the importance of these mechanisms in tumor- bearing mice and cancer patients, and will design and test novel therapeutic approaches that combine the inhibition of MDSC with the protection of T cells from the tolerizing tumor microenvironment. PUBLIC HEALTH RELEVANCE: This proposed research will determine how Myeloid-Derived Suppressor Cells (MDSC) inhibit T cells and will test new therapies designed to enhance the potential of immunotherapy for cancer patients. Cancer vaccines and cytokines can be an important therapeutic approach for patients whose tumors have failed standard forms of treatment.

描述（由申请人提供）：表达精氨酸酶（ARG）1的髓样衍生的抑制细胞（MDSC）是癌症中T细胞功能的有效抑制剂。 MDSC耗尽血清和肿瘤微环境中的L-精氨酸（L-ARG），严重损害了抗肿瘤反应。在前五年中所做的工作确定了MDSC消耗L-arg的机制，并已开始识别L-ARG耗竭导致T细胞消极的分子机制。我们发现，通过CAT转运蛋白快速掺入来表达ARG 1浸润肿瘤和耗尽L-ARG的MDSC。这种耗尽的L-arg耗尽的环境通过抑制细胞周期蛋白D3和CDK4（而不是细胞周期蛋白D2或CDK6）引起T细胞周期停滞，抑制IFNG的产生（但不是IL2），并阻止T细胞受体Z链（CD3Z）的表达，从而严重损害T细胞功能。抑制ARG 1可以重新建立增殖，IFNG产生和CD3Z表达，并触发抗肿瘤反应。这些机制是在小鼠和癌症患者中发现的。因此，我们的结果表明，L-ARG耗竭会触发对特定基因对T细胞效应功能重要的特定基因的选择性抑制，而不是从营养饥饿中蛋白质合成的普遍降低。数据还表明，这种现象是由介导这些效应机制抑制的检查点的激活引起的。因此，阻止此检查点可能会使T细胞抗MDSC的氧化/耐受作用。拟议的研究将确定由L-ARG耗竭触发的分子机制，该机制抑制了T细胞效应子功能所需的基因和蛋白质的表达。我们将证明这些机制在肿瘤轴承小鼠和癌症患者中的重要性，并将设计和测试新型的治疗方法，这些方法将MDSC抑制与保护T细胞的抑制作用，免受耐受性肿瘤微环境的影响。公共卫生相关性：这项拟议的研究将决定髓样衍生的抑制细胞（MDSC）如何抑制T细胞，并将测试旨在增强癌症患者免疫疗法潜力的新疗法。癌症疫苗和细胞因子对于肿瘤标准治疗失败的患者来说可能是一种重要的治疗方法。