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

T 细胞中吲哚胺 2,3-双加氧酶 (IDO) 诱导作为胰腺癌肿瘤诱导免疫抑制的新机制

• 批准号: 315563603
• 负责人: Privatdozent Dr. Peter Düwell
• 金额: --
• 依托单位: Institut für Angeborene Immunität
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315563603?language=en
• 关键词: Indolamin; Dioxigenase; IDO; induction; cells

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.

肿瘤建立免疫抑制性肿瘤微环境，其特征在于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，特别是细胞毒性T细胞。免疫检查点抑制剂彻底改变了肿瘤的免疫治疗，并形成了不同肿瘤实体靶向治疗的基本支柱。这些检查点之一是吲哚胺-2，3-二氧化酶（IDO），其将必需氨基酸L-色氨酸转化为免疫抑制性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由抗原递呈细胞（APC）以及肿瘤细胞表达。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抑制剂目前在早期临床试验中用于多种肿瘤实体，胰腺癌的初步数据确定了肿瘤浸润性T细胞中的IDO表达和转化生长因子-β（TGF-β）作为T细胞中IDO诱导的关键组分。这种迄今未知的机制可能有助于TGF-β介导的由T细胞中IDO间接介导的T细胞死亡（自杀）的诱导。我们的研究进一步表明，在人以及鼠CD 4+和CD 8 + T细胞中抑制IDO显著降低了由胰腺癌细胞介导的T细胞凋亡。在这个项目的范围内，我们的目标是研究胰腺癌中T细胞中TGF-β/IDO轴的详细作用。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细胞衍生的IDO在肿瘤生物学和肿瘤疫苗接种中的功能后果。通过良好表征的患者群体的组织样品，将在组织学上确定胰腺癌中的IDO表达，并将评估表达强度和定位（肿瘤细胞、APC、T细胞）与肿瘤生物学以及预后的可能相关性。为了表征IDO在肿瘤免疫学中的细胞特异性功能，将产生条件性IDO 1敲除小鼠。这种小鼠模型首次允许研究IDO在特定免疫细胞群体，特别是T细胞中的作用，并分析其对肿瘤免疫控制的影响。

项目成果

Defective Interfering Genomes and the Full-Length Viral Genome Trigger RIG-I After Infection With Vesicular Stomatitis Virus in a Replication Dependent Manner.

• DOI: 10.3389/fimmu.2021.595390
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Linder A;Bothe V;Linder N;Schwarzlmueller P;Dahlström F;Bartenhagen C;Dugas M;Pandey D;Thorn-Seshold J;Boehmer DFR;Koenig LM;Kobold S;Schnurr M;Raedler J;Spielmann G;Karimzadeh H;Schmidt A;Endres S;Rothenfusser S
• 通讯作者: Rothenfusser S

RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade

• DOI: 10.1038/s41375-019-0639-x
• 发表时间: 2019-11
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: M. Ruzicka;Lars M. Koenig;S. Formisano;D. F. Boehmer;B. Vick;Eva-M. Heuer;Hanna Meinl;Lorenz Kocheis

Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer

• DOI: 10.1186/s40425-019-0778-7
• 发表时间: 2019-11-06
• 期刊: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• 影响因子: 10.9
• 作者: Metzger, Philipp;Kirchleitner, Sabrina, V;Duewell, Peter
• 通讯作者: Duewell, Peter