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: 10341107
• 负责人: Guangyong Peng
• 金额: $ 42.23万
• 依托单位: SAINT LOUIS 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341107
• 关键词: Address; Affect; Area; Breast Cancer Patient; Cancer Etiology; Carbon; Cell Aging; 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; Investigation; Lead; 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; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Role; STAT1 gene; STAT3 gene; Signal Transduction; Source; T-Lymphocyte; TLR8 gene; Testing; Tumor Immunity; Tumor Suppression; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Woman; adaptive immunity; advanced breast cancer; anti-PD-1; base; 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; programmed cell death ligand 1; programmed cell death protein 1; 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.

项目概要/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， 调节性 T 细胞 (Treg) 诱导的免疫抑制微环境是免疫抑制的主要障碍 抗肿瘤免疫治疗取得成功。定义不同类型肿瘤使用的抑制机制 浸润性 Treg 细胞对于开发治疗人类乳腺癌的新策略至关重要。我们 最近发现肿瘤浸润淋巴细胞 (TIL) 中存在高比例的  Treg 细胞 乳腺肿瘤患者的患病率，与临床结果呈强负相关。我们进一步确定了一个  Treg 细胞诱导 T 细胞和树突状细胞 (DC) 衰老的新抑制机制 然后也会产生有效的抑制活性。因此，进一步鉴定其分子机制至关重要。 负责 Treg 诱导免疫细胞衰老的机制，然后制定策略 逆转由 Treg 细胞介导的衰老诱导。越来越多的证据表明， 淋巴细胞执行功能性免疫反应是由能量代谢途径控制的。 然而，人们对耐受性 DC 和 Treg 细胞能量代谢的调节知之甚少。我们 最近发现，Treg 细胞可以显着地重新编程 DC 脂质代谢。此外，我们观察到 TLR8 信号传导通过抑制 葡萄糖转运蛋白和糖酵解相关酶。该提案的中心假设是：1） 乳腺癌来源的 Treg 细胞重写 DC 中的脂质代谢，导致 DC 衰老 耐受性表型和功能； 2）Treg细胞和DC中代谢的重编程可以作为 协同增强肿瘤免疫治疗抗肿瘤免疫力的新策略。具体目标 1 寻求 确定 Treg 诱导的衰老 DC 中哪些脂质种类发生了变化，以及脂质的改变是否 这些成分与 DC 衰老和功能受损有因果关系。然后我们将调查 转录因子 STAT 和 PD1-PDL1 信号在控制脂质代谢紊乱中的重要性，  Treg 处理的 DC 发生衰老诱导和功能受损。具体目标 2 将确定 涉及 Treg 介导的免疫抑制并受 TLR8 调节的关键葡萄糖代谢物 人类  Treg 细胞功能逆转的信号传导。然后我们将测试 TLR8 的新颖概念 激活  Treg 细胞并结合 DC 中 PD-L1 的检查点阻断可以作为新策略 重新编程它们的代谢并协同增强乳腺癌免疫治疗的抗肿瘤免疫力。 这些研究的积极成果应该会带来新的策略来重新编程先天和适应性 未来乳腺癌免疫治疗的免疫细胞代谢。