Gamma/Delta Treg Cells and Human Breast Cancer

描述（由申请人提供）：免疫治疗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。传统的Treg细胞已被广泛研究，但γδ T细胞介导的抗肿瘤免疫应答的负性调节作用尚不清楚。我们最近发现乳腺肿瘤患者的肿瘤浸润淋巴细胞（TIL）中存在高百分比的γδ Treg细胞，其与临床结局强烈负相关。我们进一步鉴定了一种新的抑制机制，其中γδ Treg细胞诱导T细胞和树突状细胞（DC）的衰老，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诱导的衰老和抑制作用的分子机制，并开发逆转γδ Treg细胞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细胞所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。该提议的中心假设是：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，而且可以指导它们分化为具有改变的生物学功能的衰老细胞，从而放大免疫抑制; 2）由γδ Treg细胞介导的免疫抑制和衰老诱导可以被TLR 8信号传导阻断，从而导致增强的抗肿瘤免疫。具体目标1旨在确定人乳腺肿瘤源性γδ Treg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改变。然后，我们将确定ERK 1/2和p38信号传导在γδ Treg处理的应答T细胞中控制衰老诱导的重要性。目的2研究γδ Treg诱导的衰老DC介导的获得性免疫中的免疫抑制作用，并进一步探讨衰老DC致耐受功能的机制。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的肿瘤特异性有效免疫应答。目的3将首先剖析负责TLR 8信号转导介导的应答T细胞中γδ Treg抑制的逆转和衰老诱导的机制，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TLR 8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衰老肿瘤特异性T细胞的产生。这些研究的积极结果应该会导致新的策略，用于操纵γδ Treg诱导的抑制，以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.