Metabolic Control of Innate and Adaptive Immunity in Breast Cancer

项目摘要/摘要 免疫疗法是治疗晚期乳腺癌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一种主要的屏障 成功的抗肿瘤免疫治疗。定义不同类型肿瘤使用的抑制机制- 浸润性Treg细胞对于开发治疗人类乳腺癌的新策略是必不可少的。我们 新近发现在肿瘤浸润性淋巴细胞(TIL)中存在高比例的Treg细胞 乳腺癌患者的预后与临床预后呈显著负相关。我们进一步确定了一种 树突状细胞诱导T细胞和树突状细胞衰老的新机制 这也会产生强有力的抑制活动。因此，进一步进行分子鉴定是至关重要的。 Treg诱导免疫细胞衰老的机制，然后开发策略来 -Treg细胞介导的抗衰老作用。越来越多的证据表明， 淋巴细胞进行功能性免疫反应受能量代谢途径的控制。 然而，对致耐受树突状细胞和Treg细胞能量代谢的调节知之甚少。我们 最近发现，树突状细胞极大地重新编程了DC的脂质代谢。另外，我们观察到， TLR8信号通过抑制两者显著抑制人Treg细胞的糖代谢 葡萄糖转运蛋白和糖酵解相关酶。这项提议的中心假设是：1) 乳腺癌来源的树突状细胞重写DC的脂质代谢，导致DC衰老 耐受性表型和功能；2)Treg细胞和DC代谢的重新编程可作为 协同增强抗肿瘤免疫治疗肿瘤免疫的新策略。具体目标1寻求 为了确定Treg诱导的衰老树突状细胞中哪些脂质物种发生了变化，以及这种变化的脂质是否 各组分与DC衰老和功能受损有关。然后我们将调查 转录因子STAT和PD1-PDL1信号在控制脂代谢紊乱中的重要性 诱导的树突状细胞衰老和功能受损。具体目标2将确定 涉及树突状细胞介导的免疫抑制并受TLR8调控的关键葡萄糖代谢产物 人树突状细胞的功能逆转信号。然后我们将测试TLR8的新概念 树突状细胞的激活和DC中PD-L1的检查点阻断可以作为一种新的策略 重组它们的代谢，协同增强抗肿瘤免疫，用于乳腺癌的免疫治疗。 这些研究的积极结果应该会导致重新编程和适应的新策略 未来乳腺癌免疫治疗中的免疫细胞代谢。

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.