Gamma/Delta Treg Cells and Human Breast Cancer

描述(申请人提供)：免疫疗法是治疗晚期乳腺癌患者的一种很有前途的方法。然而，调节性T细胞(Treg)诱导的免疫抑制微环境是抗肿瘤免疫治疗成功的主要障碍。更好地了解不同类型的肿瘤浸润性Treg细胞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。传统的Treg细胞已被广泛研究，但对γδT细胞在肿瘤患者抗肿瘤免疫反应中的负性调节作用知之甚少。我们最近发现在乳腺癌患者的肿瘤浸润性淋巴细胞(TIL)中存在高比例的γδ树突状细胞，这与临床预后呈强烈的负相关。我们进一步确定了一种新的抑制机制，即γδ树突状细胞诱导T细胞和树突状细胞(DC)衰老，然后也产生强大的抑制活性。因此，进一步确定γδTreg诱导衰老和抑制作用的分子机制，并开发γδTreg细胞介导的逆转衰老的策略是至关重要的。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，并开发策略来修改它们的抑制作用，以改进癌症治疗。该建议的核心假设是：1)乳腺癌来源的γδ树突状细胞不仅可以直接抑制幼稚/效应T细胞和DC，而且可以引导其分化为衰老细胞，从而改变其生物学功能，放大免疫抑制；2)γδ树突状细胞介导的免疫抑制和诱导衰老可以被TLR8信号阻断，从而导致抗肿瘤免疫增强。具体目标1旨在确定人乳腺肿瘤来源的γδTreg细胞在幼稚/效应T细胞中诱导的导致T细胞衰老的分子和生物学变化。然后，我们将确定ERK1/2和p38信号在控制γδTreg处理的反应者T细胞衰老诱导中的重要性。目的研究γδ-Treg诱导的衰老树突状细胞在适应性免疫中的放大免疫抑制作用，进一步探讨衰老树突状细胞的耐受机制。然后，我们将进行体内研究，以调查γδ树突状细胞诱导的衰老树突状细胞如何影响乳腺癌模型中肿瘤特异性的有效免疫反应。目的3将首先剖析TLR8信号介导的逆转γδ树突状细胞抑制和诱导应答T细胞衰老的机制，涉及γδ树突状细胞的糖代谢变化。然后，我们将研究在乳腺癌免疫治疗模型中，通过操纵γδTreg细胞中的TLR8信号和/或葡萄糖代谢来增强抗肿瘤免疫，以防止体内衰老的肿瘤特异性T细胞的产生。这些研究的积极结果应该会导致操纵γδTreg诱导的抑制作用的新策略，用于治疗人类乳腺癌和其他癌症。

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.