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

Abstract

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.

References

  1. 1

    Mellor, A.L. & Munn, D.H. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today 20, 469–473 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Munn, D.H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Munn, D.H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Hwu, P. et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J. Immunol. 164, 3596–3599 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Kudo, Y., Boyd, C.A., Sargent, I.L. & Redman, C.W. Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation. J. Physiol. 535, 207–215 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Frumento, G., Rotondo, R., Tonetti, M. & Ferrara, G.B. T cell proliferation is blocked by indoleamine 2,3-dioxygenase. Transplant. Proc. 33, 428–430 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Fallarino, F. et al. Functional expression of indoleamine 2,3-dioxygenase by murine CD8α+ dendritic cells. Int. Immunol. 14, 65–68 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Takikawa, O., Kuroiwa, T., Yamazaki, F. & Kido, R. Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. J. Biol. Chem. 263, 2041–2046 (1988).

    CAS  PubMed  Google Scholar 

  9. 9

    Habara-Ohkubo, A., Takikawa, O. & Yoshida, R. Cloning and expression of a cDNA encoding mouse indoleamine 2,3- dioxygenase. Gene 105, 221–227 (1991).

    CAS  Article  Google Scholar 

  10. 10

    Munn, D.H. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151–155 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunol. 3, 1097–1101 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Van den Eynde, B., Lethé, B., Van Pel, A., De Plaen, E. & Boon, T. The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice. J. Exp. Med. 173, 1373–1384 (1991).

    CAS  Article  Google Scholar 

  14. 14

    Brändle, D. et al. The shared tumor-specific antigen encoded by mouse gene P1A is a target not only for cytolytic T lymphocytes but also for tumor rejection. Eur. J. Immunol. 28, 4010–4019 (1998).

    Article  Google Scholar 

  15. 15

    Medema, J.P. et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl. Acad. Sci. USA 98, 11515–11520 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Pawelec, G. et al. Escape mechanisms in tumor immunity: a year 2000 update. Crit. Rev. Oncog. 11, 97–133 (2000).

    CAS  PubMed  Google Scholar 

  17. 17

    Marincola, F., Jaffee, E.M., Hicklin, D.J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Cady, S.G. & Sono, M. 1-Methyl-DL-tryptophan, β-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys. 291, 326–333 (1991).

    CAS  Article  Google Scholar 

  19. 19

    Kudo, Y. & Boyd, C.A. Human placental indoleamine 2,3-dioxygenase: cellular localization and characterization of an enzyme preventing fetal rejection. Biochim. Biophys. Acta 1500, 119–124 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Kudo, Y. & Boyd, C.A. Characterisation of L-tryptophan transporters in human placenta: a comparison of brush border and basal membrane vesicles. J. Physiol. 531, 405–416 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Prætorius-Ibba, M. et al. Ancient adaptation of the active site of tryptophanyl-tRNA synthetase for tryptophan binding. Biochemistry 39, 13136–13143 (2000).

    Article  Google Scholar 

  22. 22

    Jorgensen, R., Sogaard, T.M.M., Rossing, A.B., Martensen, P.M. & Justesen, J. Identification and characterization of human mitochondrial tryptophanyl-tRNA synthetase. J. Biol. Chem. 275, 16820–16826 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Terness, P. et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447–457 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Fallarino, F. et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 9, 1069–1077 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Van den Eynde, B. & van der Bruggen, P. T cell-defined tumor antigens. Curr. Opin. Immunol. 9, 684–693 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Boon, T. & Van den Eynde, B. Tumor immunology—editorial overview. Curr. Opin. Immunol. 15, 129–130 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Nestle, F.O. et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat. Med. 4, 328–332 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Rosenberg, S.A. et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med. 4, 321–327 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Marchand, M. et al. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int. J. Cancer 80, 219–230 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Thurner, B. et al. Vaccination with MAGE-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J. Exp. Med. 190, 1669–1678 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Jäger, E. et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc. Natl. Acad. Sci. USA 97, 12198–12203 (2000).

    Article  Google Scholar 

  32. 32

    Suzuki, S. et al. Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3- dioxygenase in early concepti. Biochem. J. 355, 425–429 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Uno, T., Chen, P.W., Murray, T.G., Podack, E.R. & Ksander, B.R. Gene transfer of the CD80 costimulatory molecule into ocular melanoma cells using a novel episomal vector. Invest. Ophtalmol. Vis. Sci. 38, 2531–2539 (1997).

    CAS  Google Scholar 

  34. 34

    Wenkel, H., Chen, P.W., Ksander, B.R. & Streilein, J.W. Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts placed in the subretinal space. Invest. Opthalmol. Vis. Sci. 40, 3202–3208 (1999).

    CAS  Google Scholar 

  35. 35

    Lethé, B., Van den Eynde, B., Van Pel, A., Corradin, G. & Boon, T. Mouse tumor rejection antigens P815A and P815B: two epitopes carried by a single peptide. Eur. J. Immunol. 22, 2283–2288 (1992).

    Article  Google Scholar 

  36. 36

    Van Pel, A., De Plaen, E. & Boon, T. Selection of a highly transfectable variant from mouse mastocytoma P815. Som. Cell Genet. 11, 467–475 (1985).

    CAS  Article  Google Scholar 

  37. 37

    Bilsborough, J. et al. TNF-mediated toxicity after massive induction of specific CD8+ T cells following immunization of mice with a tumor-specific peptide. J. Immunol. 169, 3053–3060 (2002).

    CAS  Article  Google Scholar 

  38. 38

    Van den Eynde, B. et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J. Exp. Med. 182, 689–698 (1995).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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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