Indolamin-2,3-Dioxigenase (IDO) induction in T cells as new mechanism of tumor-induced immunosuppression in pancreatic carcinoma

肿瘤建立了免疫抑制性肿瘤微环境，其特征是调节性免疫细胞群的浸润、免疫抑制性细胞因子的分泌和检查点分子的表达。这使得肿瘤能够躲避免疫识别，尤其是细胞毒性T细胞的识别。免疫检查点抑制剂彻底改变了肿瘤的免疫治疗，形成了不同肿瘤实体靶向治疗的基本支柱。其中一个检查点是吲哚胺-2,3-二氧合酶（IDO），它将必需氨基酸l -色氨酸转化为免疫抑制剂l -犬尿氨酸。IDO是保护子宫内胎儿的母体免疫系统的重要组成部分。肿瘤利用IDO逃避免疫识别。在肿瘤微环境中，IDO既通过抗原呈递细胞（antigen-presenting cells， APC）表达，也通过肿瘤细胞表达。ido介导的l -色氨酸耗竭导致T细胞增殖抑制。此外，新出现的代谢产物犬尿氨酸通过芳烃受体（AhR）诱导T细胞凋亡。IDO抑制剂目前正在不同肿瘤实体的早期临床试验中探索。在胰腺癌的初步数据中发现IDO在肿瘤浸润的T细胞中表达，转化生长因子- β (tgf - β)是T细胞中IDO诱导的关键成分。这一迄今未知的机制可能有助于tgf - β介导的T细胞死亡（自杀）的诱导，而T细胞死亡是由IDO间接介导的。我们的研究进一步表明，在人及小鼠CD4+和CD8+ T细胞中，IDO的抑制可显著减少胰腺癌细胞介导的T细胞凋亡。在这个项目的范围内，我们的目标是研究tgf - β /IDO轴在胰腺癌T细胞中的详细作用。为了验证这一假设，我们利用多种体外和体内模型来研究T细胞中IDO的调节以及T细胞来源的IDO在肿瘤生物学和肿瘤疫苗接种中的功能后果。通过具有良好特征的患者群体的组织样本，将从组织学上确定IDO在胰腺癌中的表达，并评估表达强度和定位（肿瘤细胞、APC、T细胞）与肿瘤生物学和预后的可能相关性。为了表征IDO在肿瘤免疫学中的细胞特异性功能，我们将生成条件ido1敲除小鼠。该小鼠模型首次允许研究IDO在特定免疫细胞群，特别是T细胞中的作用，并分析其对肿瘤免疫控制的影响。

Tumors establish an immunosuppressive tumor microenvironment, characterized by the infiltration of regulatory immune cell populations, secretion of immunosuppressive cytokines and expression of checkpoint molecules. This enables tumors to hide from immune recognition, especially by cytotoxic T cells. Immune checkpoint inhibitors revolutionized the immunotherapy of tumors and form a fundamental pillar in targeted therapies of different tumor entities. One of these checkpoints is the enzyme indoleamin-2,3-dioxigenase (IDO), which converts the essential amino acid L-tryptophan into immunosuppressive L-kynurenines. IDO is an important component of the maternal immune system protecting the fetus within the uterus. Tumors make use of IDO to evade immune recognition. In the tumor microenvironment, IDO is expressed by antigen-presenting cells (APC), as well as tumor cells. IDO-mediated depletion of L-tryptophan leads to inhibition of T cell proliferation. Additionally, emerging metabolites, the kynurenines, induce T cell apoptosis via the aryl hydrocarbon receptor (AhR). IDO inhibitors are currently explored in early phase clinical trials for diverse tumor entities.Own preliminary data in pancreatic carcinoma identified IDO expression in tumor-infiltrating T cells and transforming growth factor-beta (TGF-beta) as a key component for IDO induction in T cells. This so far unknown mechanism could contribute to TGF-beta-mediated induction of T cell death (suicide) indirectly mediated by IDO in T cells. Our studies further show that inhibition of IDO, in human as well as murine CD4+ and CD8+ T cells, significantly reduces T cell apoptosis mediated by pancreatic carcinoma cells. Within the scope of this project we aim at investigating the detailed role of the TGF-beta/IDO axis in T cells within pancreatic carcinoma. To test this hypothesis, we utilize diverse in vitro as well as in vivo models for investigating the regulation of IDO in T cells as well as functional consequences of T cell-derived IDO in tumor biology and tumor vaccination. By means of tissue samples of a well-characterized patient population, IDO expression in pancreatic carcinoma will be determined histologically and possible correlations of expression intensity and localization (tumor cells, APC, T cells) with tumor biology as well as prognosis will be assessed. In order to characterize cell-specific functions of IDO in tumor immunology, a conditional IDO1-knockout mouse will be generated. This mouse model allows for the first time to investigate the role of IDO in specific immune cell populations, particularly T cells, and to analyze its influence on the immune control of tumors.