Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees?

Abstract

Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme capable of inhibiting a destructive maternal T cell response against allogeneic fetuses. Expression of IDO is evident in tumours and is thought to enable escape from immunologically mediated rejection. Consequently, clinical trials using an inhibitor of IDO, 1-methyltryptophan (1MT), have been initiated. However, a review of the current literature indicates that we are far from understanding the biological relevance of IDO expression during tumorigenesis. A better understanding of IDO biology is needed to comprehend the effect of IDO inhibitors and to provide a rationale for their therapeutic application in cancer.

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

“…We previously observed in a preclinical model that rejection of IDO1-expressing tumors was promoted by systemic treatment with an IDO1 inhibitor (4). The search for IDO1 inhibitors that can be used clinically is ongoing (7,(28)(29)(30). We show here that tumors also use another means to degrade tryptophan and resist immune rejection: they express TDO, the tryptophan-degrading enzyme normally expressed almost exclusively in the liver.…”

“…IDO1 has been the focus of attention in recent years because of its immunosuppressive effects on T lymphocytes, resulting partly from tryptophan depletion and partly from direct effects of tryptophan catabolites (1)(2)(3). IDO1 is expressed constitutively in the placenta, where it plays a key role in feto-maternal tolerance (2), and in many tumors, where it contributes to tumoral resistance to immune rejection (4)(5)(6)(7). IDO1 expression is also inducible in many cells, including dendritic cells, and appears to play a role in peripheral immune tolerance and the retro-control of immune responses (8).…”

IDO1 Plays an Immunosuppressive Role in 2,4,6-Trinitrobenzene Sulfate–Induced Colitis in Mice

“…In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine, which is the first and rate-controlling step in the kynurenine pathway (1). IDO exerts immunosuppressive effects by reducing the local concentration of tryptophan and increasing the production of immunomodulatory tryptophan metabolites, which have a variety of effects on immune cells.…”

Drugs that Kill Cancer Stem-like Cells

“…This is a highly interesting result, which suggests that CSCs are endowed with activity that results in lowering the level of tryptophan in their 'neighborhood'. Depletion of tryptophan (especially due to upregulation of IDO) is one way how cancer cells may protect themselves from the immune surveillance, providing the cancer cells with both passive and active defense mechanisms (Munn & Melor, 2008;Löb et al, 2009), and inhibitors of IDO, such as brassinin or 1-methyl tryptophan, are being considered as anti-cancer drugs (Gaspari et al, 2006;Hou et al, 2007). It is therefore very tempting to speculate that a highly efficient way to eradicate tumour cells, including the fast-proliferating ones and the resistant CSCs, may be the combination of agents like MitoVES that would kill the bulk of the tumour cells, while the IDO inhibitor would allow for the cells of the immune system to attack the remaining tumour cells, likely those with higher level of 'stemness'.…”