Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase


T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degradation. Here we show that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.

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Figure 1: Constitutive expression and activity of IDO in human cancer cell lines.
Figure 2: Expression of IDO protein in human tumors.
Figure 3: Immune resistance of IDO-expressing tumors.
Figure 4: Reversal of immune resistance by systemic inhibition of IDO.


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We thank J. Bilsborough, S. Buonocore, F. Brasseur, P. Camby, D. Donckers, C. Jacques, B. Lethé, F. Piette and G. Warnier for help at various steps of the work; S. Depelchin for editorial assistance; and P. Coulie and P. van der Bruggen for critical reading of the manuscript. This work was supported in part by a grant from FB Assurances and VIVA (Belgium), and by grants QLG1-CT-1999-00622, QLK2-CT-1999-00556 and QLK2-CT-1999-00318 from the Fifth Framework programme of the European Community.

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Correspondence to Benoît J Van den Eynde.

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Uyttenhove, C., Pilotte, L., Théate, I. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9, 1269–1274 (2003). https://doi.org/10.1038/nm934

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