Targeting the Indoleamine 2,3-Dioxygenase Pathway to Suppress Pancreatic Ductal Adenocarcinoma Metastasis
Introduction. Pancreatic ductal adenocarcinoma (PDAC) remains as one of the deadliest types of cancer, with 5-year survival rates remaining around 3% (1). PDAC tends to metastasize earlier than other types of cancer, so the efficacy of traditional first-line cancer treatments such as surgical resection and radiation therapy is diminished (2). Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that initiates the first step for tryptophan degradation along the kynurenine pathway (3). Consumption of tryptophan through the IDO pathway induces T cell anergy and enhances Treg function (3). Both the downregulation of effector T cell function and the upregulation of Tregs is important in the pathogenesis of PDAC, which has been shown to create a microenvironment that suppresses the immune system to allow for PDAC proliferation and metastasis (4). Methods. Using a mixed lymphocyte tumor cell culture (MLTC), researchers correlated the levels of IDO expression induced in tumor cells with T cell proliferation and activation using RT-qPCR (5). Cultures of lung adenocarcinoma (A549) and cervical adenocarcinoma (HeLa) were transfected with scrambled short hairpin RNA (shRNA) or anti-IDO shRNA and subsequently treated with gamma radiation and olaparib (6). Proliferation levels were quantified using a BD FACSCalibur flow cytometer and FlowJo software (6). Western blot and immunohistochemistry staining for IDO antiserum were positive for the presence of IDO in PDAC tissues (7). Patients were stratified by IDO expression levels and followed for 50 months and results were plotted on a Kaplan-Meier survival curve (7). Results. IDO expression levels were inversely correlated with the expansion rate of T cells in the MLTC and directly correlated with the capacity of tumor cells to inhibit T cell activation (5). The addition of an IDO inhibitor, 1-methyl-tryptophan (1-MT) to the MLTC partly restored the tumor-induced inhibition of T cell activation (5). IDO knockdowns had significantly lower rates of proliferation in the presence of cancer therapeutics compared to cells with intact IDO pathways (p<0.05) (6). Patients with high IDO expression levels in PDAC tissue had significantly poorer prognosis compared to patients with low IDO expression (p<0.01) (7). Conclusions. Studies have found that the IDO pathway is an important mediator in the pathogenesis of PDAC. Based on these results, the IDO pathway provides another promising avenue for treating PDAC. Given the heterogeneity of the PDAC microenvironment, combination therapies including an IDO inhibitor may become the preferred method of treatment.
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