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（由适用提供）：免疫疗法是治疗晚期乳腺癌患者的有希望的方法。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疗法的主要障碍。更好地理解不同类型的肿瘤浸润Treg细胞所使用的抑制机制，对于制定珍藏人类癌症的新型策略至关重要。但是，常规的Treg细胞已广泛研究，但是，关于癌症患者抗肿瘤免疫调查中γδT细胞介导的负调控知之甚少。最近，我们发现乳腺肿瘤患者肿瘤浸润淋巴细胞（TIL）中存在的γδTreg细胞很高，这与临床结局密切相关。我们进一步确定了一种新型的抑制机制，从而γδTreg细胞在T细胞和树突状细胞（DC）中诱导感应，然后发展潜在的抑制活性。因此，至关重要的是要进一步识别负责γδTreg诱导的感应和抑制作用的分子机制，并制定策略以逆转由γδTreg细胞介导的感应。我们的长期目标是确定与肿瘤相关的Treg细胞使用的免疫调节机制，并制定策略以改变其抑制作用以改善癌症治疗。该提案的中心假设是：1）乳腺肿瘤衍生的γδTreg细胞不仅可以直接抑制幼稚/效应的T细胞和DC，而且可以将其分化引导为具有改变的生物学功能的感觉细胞，从而扩大免疫抑制； 2）可以通过TLR8信号传导阻断由γδTreg细胞介导的免疫抑制和感应诱导，从而导致抗肿瘤免疫组织化学增强。特定目标1旨在确定幼稚 /效应T细胞中人类乳腺肿瘤衍生的γδTreg细胞引起的分子和生物学改变，从而导致T细胞感受。然后，我们将确定ERK1/2和P38信号传导在控制经过γδTreg处理的响应者T细胞中的重要性。 AIM 2将研究由γδTreg诱导的感官DC介导的自适应免疫组织化学中的放大器免疫抑制，并进一步确定了导致感官DC耐受性功能的机制。然后，我们将进行体内研究，以研究γδTreg诱导的感觉DC如何影响乳腺癌模型中肿瘤特异性免疫复杂。 AIM 3将首先剖析负责TLR8信号传导介导的机制，从而在γδTreg细胞中涉及葡萄糖代谢变化的反应T细胞中抑制γδTreg抑制和感觉。然后，我们将通过操纵TLR8信号传导和/或葡萄糖代谢在γδTREG细胞中，以防止在乳腺癌免疫疗法模型中生成感觉肿瘤特异性T细胞的γδTREG细胞中，研究抗肿瘤免疫辅助的增强。这些研究的积极结果应导致对操纵γδTreg诱导的抑制作用的新策略，以治疗人类乳腺癌和其他癌症。