IN THE SPOTLIGHT Turn Off the IDO: Will Clinical Trials Be Successful?

Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that is highly expressed in myeloid cells (e.g., macrophages, dendritic cells) and catalyzes the initial step in tryptophan degradation by the kynurenine pathway. Tryptophan starvation by IDO activation inhibits T-cell function by several mechanisms. First, tryptophan depletion can directly lead to T-cell growth arrest in the G1 phase of the cell cycle. Second, alternative degradation of tryptophan produces metabolites shown to be toxic for CD8+ T cells and natural killer cells. Furthermore, IDO has the ability to convert naïve T cells to immunosuppressive regulatory T cells (1). IDO also triggers phosphorylation of the translation-initiating factor eIF2a and mobilizes translation of LIP, the inhibitory form of the immunoregulatory transcription factor LAP/NF-IL6/CEBPβ. An increasing number of studies have linked overexpression of IDO to cancer progression. High levels of IDO expression are found in patients with ovarian carcinoma, hepatocellular carcinoma, invasive cervical carcinoma, non–small cell lung carcinoma, colon carcinoma, and endometrial carcinoma and are associated with poor prognosis (2). IDO localizes both in tumor sites, where depletion of tryptophan reduces the effector function of T cells, and in tumor-draining lymph nodes, where IDO-expressing plasmacytoid dendritic cells have a tolerogenic effect on T cells during their encounter with antigen-loading antigen-presenting cells. Increased IDO in tumor cells can be a part of the global changes involved in malignant transformation such as downregulation of BIN1, which controls IDO expression (3), and may also be a component of the response to infl ammatory cytokines, as IDO is known to be induced by IFN-γ (4). In vitro studies using human monocyte-derived macrophages showed that an increased level of IDO can suppress proliferation of T cells as well as monocyte-derived dendritic cells, thus reducing the immune response. Together with those terminally IN THE SPOTLIGHT Turn Off the IDO: Will Clinical Trials Be Successful? Sergey V. Novitskiy and Harold L. Moses Summary: Indoleamine 2,3-dioxygenase (IDO) is overexpressed in many human cancers and is believed to play a role in tumor immune evasion, but a requirement for IDO in tumor progression has not been formally shown. The study by Smith and colleagues in this issue of Cancer Discovery provides genetic evidence for the importance of IDO in tumorigenesis, which supports the use of IDO inhibitors in clinical trials in humans. Cancer Discov; 2(8); 673–5. ©2012 AACR.