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Review
. 2007 May;117(5):1147-54.
doi: 10.1172/JCI31178.

Indoleamine 2,3-dioxygenase and tumor-induced tolerance

David H Munn  1 , Andrew L Mellor
Affiliations
Review

Indoleamine 2,3-dioxygenase and tumor-induced tolerance

David H Munn et al. J Clin Invest. 2007 May.

Abstract

Tumors arise from normal cells of the body through genetic mutation. Although such genetic mutation often leads to the expression of abnormal antigens, the immune system fails to respond effectively to these antigens; that is, it is tolerant of these antigens. This acquired state of tolerance must be overcome for cancer immunotherapy to succeed. Indoleamine 2,3-dioxygenase (IDO) is one molecular mechanism that contributes to tumor-induced tolerance. IDO helps create a tolerogenic milieu in the tumor and the tumor-draining lymph nodes, both by direct suppression of T cells and enhancement of local Treg-mediated immunosuppression. It can also function as an antagonist to other activators of antitumor immunity. Therefore, strategies to block IDO might enhance the effectiveness of tumor immunotherapy.

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Figures

Figure 1
Figure 1. Molecular mechanisms of IDO-induced immunosuppression.
(A) IDO catalyzes the initial and rate-limiting step in the degradation of tryptophan along the kynurenine pathway. Tryptophan metabolites have been shown to have immunomodulatory activity, alone or in combination with the GCN2 signaling pathway. (B) IDO enzymatic activity results in the local depletion of tryptophan and a local increase in the concentration of downstream metabolites. The decrease in tryptophan can cause a rise in the level of uncharged transfer RNA (tRNA) in neighboring T cells, resulting in activation of the amino acid–sensitive GCN2 stress-kinase pathway. In turn, GCN2 signaling can cause cell cycle arrest and anergy induction in responding T cells. The local increase in tryptophan metabolites can cause cell cycle arrest, apoptosis, and (in conjunction with GCN2 signaling) differentiation of new Tregs from uncommitted CD4+ T cells.
Figure 2
Figure 2. Model of the effects of IDO in tumors and tumor-draining lymph nodes.
(A) In tumor-draining lymph nodes, IDO-expressing DCs directly suppress and anergize tumor-reactive effector T cells responding to antigens presented by IDO+ DCs. Also, through bystander suppression, IDO can inhibit T cell responses to antigens presented by neighboring APCs. One mechanism that can induce IDO expression in DCs is reverse signaling mediated by B7-1 or B7-2 molecules expressed on DCs binding to CTLA4 expressed on Tregs. Reciprocally, IDO expression by DCs can also activate Tregs and drive the differentiation of new Tregs from uncommitted CD4+ T cells. (B) In the tumor microenvironment, tumor cells can either express IDO constitutively or upregulate IDO in response to inflammatory signals generated by activated effector T cells. IDO expression by tumor cells inhibits effector T cells and also activates Tregs to further contribute to the suppressive microenvironment within the tumor.
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