Metabolic Control of Innate and Adaptive Immunity in Breast Cancer

项目总结/摘要 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，在这方面， 由调节性T细胞（Treg）诱导的免疫抑制微环境呈现出免疫抑制的主要障碍， 成功的抗肿瘤免疫疗法。定义不同类型肿瘤的抑制机制- 浸润性Treg细胞对于开发治疗人乳腺癌的新策略是必需的。我们 最近发现，肿瘤浸润性淋巴细胞（TIL）中存在高百分比的凋亡性Treg细胞， 乳腺肿瘤患者，这是强烈的负相关的临床结果。我们进一步确定了一个 一种新的抑制机制，其中，活化的Treg细胞诱导T细胞和树突状细胞（DC）中的衰老 也会产生有效的抑制活性。因此，进一步鉴定其分子结构至关重要。 在免疫细胞中，负责抗肿瘤Treg诱导衰老的机制，然后制定策略， 逆转衰老诱导，其通过活化的Treg细胞介导。越来越多的证据表明， 淋巴细胞执行功能性免疫应答是由能量代谢途径控制的。 然而，对致耐受性DC和Treg细胞中能量代谢的调节知之甚少。我们 最近发现，树突状Treg细胞显著地重编程DC脂质代谢。此外，我们观察到， TLR 8信号转导通过抑制两种途径显著抑制人巨噬细胞Treg细胞中的葡萄糖代谢。 葡萄糖转运蛋白和糖酵解相关酶。该建议的核心假设是：1） 乳腺癌来源的树突状细胞Treg细胞重写DC中的脂质代谢，导致DC衰老， 致耐受性表型和功能; 2）Treg细胞和DC中代谢的重编程可以作为免疫调节剂。 协同增强抗肿瘤免疫用于肿瘤免疫治疗的新策略。具体目标1寻求 为了确定在树突状细胞Treg诱导的衰老DC中哪些脂质种类发生了变化，以及改变的脂质是否 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PD 1-PDL 1信号在控制脂质代谢紊乱中的重要性， 在经Treg处理的DC中发生衰老诱导和功能受损。具体目标2将确定 涉及EGFR Treg介导的免疫抑制并受TLR 8调节的关键葡萄糖代谢物 在人树突状Treg细胞中用于功能逆转的信号传导。然后，我们将测试TLR 8 活化树突状细胞Treg细胞与阻断DC中PD-L1的检查点相结合可以作为新的策略， 重新编程它们的代谢并协同增强乳腺癌免疫疗法的抗肿瘤免疫。 这些研究的积极结果应该会导致新的策略来重新编程先天和适应性 免疫细胞代谢用于未来乳腺癌免疫治疗。

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.