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

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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.