Metabolic Control of Innate and Adaptive Immunity in Breast Cancer

乳腺癌先天性和适应性免疫的代谢控制

• 批准号: 10547790
• 负责人: Guangyong Peng
• 金额: $ 43.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547790
• 关键词: Address; Affect; Area; Breast Cancer Patient; Cancer Etiology; Carbon; Cell Aging; Cell Senescence Induction; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Cholesterol; Clinical; Dendritic Cells; Development; Energy Metabolism; Energy Metabolism Pathway; Enzymes; Future; Glucose; Glucose Transporter; Glycolysis; Goals; Human; Immune; Immune response; Immunosuppression; Immunotherapy; Impairment; Infiltration; Investigation; Link; Lipids; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Molecular; Natural Immunity; Outcome; Outcome Study; PD-1/PD-L1; PD-L1 blockade; Patients; Phenotype; Proliferating; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Role; STAT1 gene; STAT3 gene; Signal Transduction; Source; T-Cell Activation; T-Lymphocyte; TLR8 gene; Testing; Tumor Immunity; Tumor Suppression; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Woman; Writing; adaptive immunity; advanced breast cancer; anti-PD-1; cancer immunotherapy; cancer therapy; fatty acid oxidation; glucose metabolism; glucose transport; immune checkpoint blockade; immunogenicity; immunosenescence; improved; in vivo; lipid metabolism; malignant breast neoplasm; neoplasm immunotherapy; novel; novel strategies; programs; response; senescence; transcription factor; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Immunotherapy is a promising approach for treating patients with advanced breast cancer. However, immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier to successful anti-tumor immunotherapy. Defining the suppressive mechanisms used by different types of tumor- infiltrating Treg cells is essential for the development of novel strategies to treat human breast cancer. We recently discovered high percentages of  Treg cells existing among the tumor-infiltrating lymphocytes (TILs) of breast tumor patients, which are strongly negatively correlated with clinical outcomes. We further identified a novel suppressive mechanism whereby  Treg cells induce senescence in T cells and dendritic cells (DCs) that then also develop potent suppressive activity. Therefore, it is critical to further identify the molecular mechanisms responsible for  Treg-induced senescence in immune cells, and then to develop strategies to reverse senescence induction mediated by  Treg cells. Increasing evidence indicates that the ability of a lymphocyte to perform functional immune responses is controlled by pathways of energy metabolism. However, little is known about the regulation of energy metabolism in tolerogenic DCs and Treg cells. We recently found that  Treg cells dramatically reprogram DC lipid metabolism. In addition, we observed that TLR8 signaling significantly suppresses glucose metabolism in human  Treg cells via inhibition of both glucose transporters and glycolysis-related enzymes. The central hypotheses of this proposal are that: 1) breast cancer-derived Treg cells rewrite lipid metabolism in DCs, resulting in DC senescence with tolerogenic phenotypes and functions; 2) reprogramming of metabolism in Treg cells and DCs can serve as a novel strategy to synergistically enhance anti-tumor immunity for tumor immunotherapy. Specific Aim 1 seeks to identify what lipid species are changed in  Treg-induced senescent DCs and whether the altered lipid components are causatively related to the DC senescence and impaired functions. We will then investigate the importance of transcription factor STAT and PD1-PDL1 signaling in controlling lipid metabolism disorder, senescence induction and impaired functions occurred in  Treg-treated DCs. Specific Aim 2 will identify the key glucose metabolites that involve  Treg-mediated immune suppression and are regulated by TLR8 signaling for functional reversal in human  Treg cells. We will then test the novel concept that TLR8 activation in  Treg cells combined with checkpoint blockade of PD-L1 in DCs can serve as novel strategies to reprogram their metabolism and synergistically enhance anti-tumor immunity for breast cancer immunotherapy. A positive outcome from these studies should lead to novel strategies to reprogram innate and adaptive immune cell metabolism for future breast cancer immunotherapy.

项目摘要/摘要 免疫疗法是治疗晚期乳腺癌患者的一种有前途的方法。然而， 由调节性T细胞（TREG）诱导的免疫抑制微环境呈现出主要的障碍 成功的抗肿瘤免疫疗法。定义不同类型的肿瘤使用的抑制机制 浸润Treg细胞对于制定治疗人类乳腺癌的新策略至关重要。我们 最近发现，在肿瘤浸润淋巴细胞（TILS）中存在的treg细胞中很高的treg细胞比例很高。 乳腺肿瘤患者与临床结局密切相关。我们进一步确定了 新型抑制机制，Treg细胞在T细胞和树突状细胞（DC）中诱导感应 然后，这也发展了潜在的抑制活性。因此，至关重要的是进一步识别分子 负责免疫电池中Treg诱导的感应的机制，然后制定策略 由treg细胞介导的反向感应诱导。越来越多的证据表明 进行功能免疫反应的淋巴细胞由能量代谢途径控制。 然而，对于耐受性DC和Treg细胞中能量代谢的调节知之甚少。我们 最近发现，treg细胞动态重编程DC脂质代谢。另外，我们观察到 TLR8信号传导通过抑制两种 葡萄糖转运蛋白和糖酵解相关酶。该提议的中心假设是：1） 乳腺癌衍生的treg细胞在DC中重写脂质代谢，从而导致DC感应 耐受性表型和功能； 2）重新编程Treg细胞和DC中的代谢可以用作 协同增强肿瘤免疫疗法的抗肿瘤免疫疗法的新型策略。特定目标1寻求 确定在treg诱导的Senscent DC中改变了哪些脂质物种以及是否改变脂质 组件与直流感应和功能受损严重相关。然后，我们将调查 转录因子Stat和PD1-PDL1信号在控制脂质代谢障碍中的重要性， 在Treg处理的DC中发生衰老诱导和功能受损。特定目标2将确定 关键葡萄糖代谢产物，涉及Treg介导的免疫抑制，由TLR8调节 人类treg细胞中功能逆转的信号传导。然后，我们将测试TLR8的新颖概念 treg细胞中的激活与DC中的PD-L1的检查点阻塞可以充当新的策略 重新编程其新陈代谢并协同增强乳腺癌的抗肿瘤免疫疗法。 这些研究的积极结果应导致重新编程先天和适应性的新策略 免疫细胞代谢用于未来的乳腺癌免疫疗法。