Gamma/Delta Treg Cells and Human Breast Cancer

γ/δ Treg 细胞与人类乳腺癌

• 批准号: 9024480
• 负责人: Guangyong Peng
• 金额: $ 34.66万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024480
• 关键词: Address; Affect; Animal Model; Area; Biological; Biological Process; Breast; Breast Cancer Model; Breast Cancer Patient; Cancer Etiology; Cancer Patient; Cell Aging; Cells; Cessation of life; Clinical; DNA Damage; Dendritic Cells; Development; Diploid Cells; Energy Metabolism; Equilibrium; Functional disorder; Future; Gene Expression Regulation; Generations; Goals; Growth; Health; Human; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Intervention; Investigation; Lead; MAPK11 gene; MAPK3 gene; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Natural Immunity; Outcome; Outcome Study; Patients; Phenotype; Process; Public Health; Regulation; Regulatory T-Lymphocyte; Research; Signal Transduction; T cell anergy; T-Lymphocyte; TLR8 gene; Telomerase; Telomere Shortening; Therapeutic; Tumor Immunity; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Woman; adaptive immunity; cancer immunotherapy; cancer therapy; glucose metabolism; immunosenescence; improved; in vivo; malignant breast neoplasm; neoplasm immunotherapy; novel; novel strategies; prevent; response; senescence; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): 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. A better understanding of the suppressive mechanisms utilized by different types of tumor-infiltrating Treg cells is essential for the development of novel strategies to trea human cancers. Conventional Treg cells have been extensively studied, however, little is known about the negative regulation mediated by γδ T cells in anti-tumor immune responses in cancer patients. We recently discovered high percentages of γδ 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 γδ 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 γδ Treg-induced senescence and suppressive effects, and to develop strategies to reverse senescence induction mediated by γδ Treg cells. Our long-term goals are to identify the immunoregulatory mechanisms utilized by tumor-associated Treg cells and develop strategies to modify their suppressive effects for improved cancer treatment. The central hypotheses of this proposal are that: 1) breast tumor-derived γδ Treg cells not only can directly suppress naïve/effector T cells and DCs, but also can direct their differentiation into senescent cells with altered biological functions that amplify immune suppression; 2) immune suppression and senescence induction mediated by γδ Treg cells can be blocked by TLR8 signaling, thereby resulting in enhanced anti-tumor immunity. Specific Aim 1 seeks to determine the molecular and biological alterations induced by human breast tumor-derived γδ Treg cells in naïve /effector T cells leading to T cell senescence. We will then identify the importance of ERK1/2 and p38 signaling in controlling senescence induction in γδ Treg-treated responder T cells. Aim 2 will investigate the amplified immune suppression in adaptive immunity mediated by γδ Treg-induced senescent DCs and further identify the mechanisms responsible for the tolerogenic functions of senescent DCs. We will then perform in vivo studies to investigate how γδ Treg- induced senescent DCs affect tumor-specific effective immune responses in breast cancer models. Aim 3 will first dissect the mechanisms responsible for TLR8 signaling-mediated reversal of γδ Treg suppression and senescence induction in responder T cells involving glucose metabolism changes in γδ Treg cells. We will then investigate the enhancement of anti-tumor immunity through manipulation of TLR8 signaling and/or glucose metabolism in γδ Treg cells preventing generation of senescent tumor-specific T cells in vivo in breast cancer immunotherapy models. A positive outcome from these studies should lead to novel strategies for manipulation of γδ Treg-induced suppression for the treatment of human breast cancer and other cancers as well.

描述（由申请人提供）：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成功抗肿瘤免疫治疗的主要障碍。更好地了解不同类型的肿瘤浸润性 Treg 细胞所利用的抑制机制对于开发治疗人类癌症的新策略至关重要。常规Treg细胞已被广泛研究，然而，人们对γδT细胞在癌症患者抗肿瘤免疫反应中介导的负调节知之甚少。我们最近发现乳腺肿瘤患者的肿瘤浸润淋巴细胞（TIL）中存在高比例的γδ Treg细胞，这与临床结果呈强负相关。我们进一步确定了一种新的抑制机制，通过该机制，γδ Treg 细胞诱导 T 细胞和树突状细胞 (DC) 衰老，然后这些细胞也产生有效的抑制活性。因此，进一步确定 γδ Treg 诱导衰老和抑制作用的分子机制，并制定逆转 γδ Treg 介导的衰老诱导的策略至关重要。我们的长期目标是确定肿瘤相关 Treg 细胞利用的免疫调节机制，并制定策略来改变其抑制作用，以改善癌症治疗。该提案的中心假设是：1）乳腺肿瘤来源的γδ Treg细胞不仅可以直接抑制幼稚/效应T细胞和DC，还可以引导其分化为生物功能改变的衰老细胞，从而放大免疫抑制； 2）TLR8信号可以阻断γδ Treg细胞介导的免疫抑制和衰老诱导，从而增强抗肿瘤免疫力。具体目标 1 旨在确定人乳腺肿瘤来源的 γδ Treg 细胞在幼稚/效应 T 细胞中诱导导致 T 细胞衰老的分子和生物学改变。然后，我们将确定 ERK1/2 和 p38 信号传导在控制 γδ Treg 处理的应答 T 细胞衰老诱导中的重要性。目标 2 将研究 γδ Treg 诱导的衰老 DC 介导的适应性免疫中放大的免疫抑制，并进一步确定衰老 DC 的耐受功能的机制。然后，我们将进行体内研究，以研究γδ Treg 诱导的衰老 DC 如何影响乳腺癌模型中肿瘤特异性的有效免疫反应。目标 3 将首先剖析 TLR8 信号介导的 γδ Treg 抑制逆转和应答 T 细胞衰老诱导的机制，涉及 γδ Treg 细胞中的葡萄糖代谢变化。然后，我们将研究通过操纵 γδ Treg 细胞中的 TLR8 信号传导和/或葡萄糖代谢来增强抗肿瘤免疫，从而防止乳腺癌免疫治疗模型中体内产生衰老的肿瘤特异性 T 细胞。这些研究的积极成果应该会带来新的策略来操纵 γδ Treg 诱导的抑制，以治疗人类乳腺癌和其他癌症。