IDO/TDO Inhibition in Cancer

Elevated tryptophan catabolism in many human tumors occurs due to activation of indoleamine 2,3-dioxygenase-1 (IDO1) or tryptophan dioxygenase (TDO), structurally distinct enzymes which drive multifaceted processes of immunosuppression, neovascularization, and metastatic progression. Immunosuppression by IDO1 involves suppression of local CD8+ T effector cells and natural killer cells along with induction of CD4+ T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC). While less studied, TDO, like IDO1, is implicated in immune escape and metastatic progression, and emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated Treg function and perhaps contribute to B-cell inflamed states in certain cancers. IDO1 and TDO are overexpressed primarily in neoplastic cells in tumors, but they are also elevated variably in stromal, endothelial, and innate immune cells of the tumor microenvironment and in tumor-draining lymph nodes in different human cancers. Preclinical pharmacological and genetic studies validated IDO1 as a therapeutic target in cancer as combined with “immunogenic” chemotherapy or immune checkpoint modalities. Mechanistic investigations encourage the concept that IDO/TDO function is rooted in inflammatory programming, including as support for tumor neovascularization, MDSC generation, and metastasis beyond established effects on adaptive immune tolerance. Discovery and development of small-molecule enzyme inhibitors of IDO1 derived from the hydroxylamidine and phenylimidazole chemotypes have advanced furthest to date in phase II/III trials (epacadostat and GDC-0919, respectively). TDO inhibitors and second-generation “tunable” IDO/TDO inhibitors being pursued may broaden impact in cancer treatment, for example, in addressing IDO1 bypass (inherent resistance) or acquired resistance to IDO1 inhibitors. This chapter focuses on work from preclinical pioneers of the first bioactive IDO inhibitors as a novel class of small-molecule drugs to reprogram inflammation and degrade a key immune escape pathway in cancer.