SpringerLink
Log in

Role of Kynurenine Pathway in Hematological Malignancies

  • Chapter
Targeting the Broadly Pathogenic Kynurenine Pathway

  • 989 Accesses

Abstract

Similarly to solid tumors, hematological malignancies create an immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated. Some recent reports have shed new light on the mechanisms underlying the induction of immunological tolerance by leukemic cells. Among these, tryptophan catabolism toward kynurenines by indoleamine 2,3-dioxygenase 1 (IDO1) has been recently described as a potent immunosuppressive pathway in several hematological tumors. The first evidence of a role of kynurenine pathway in regulating immune escape was described in acute myeloid leukemia (AML). Such preliminary finding has been recently extended to pediatric leukemias and Hodgkin and non-Hodgkin lymphomas. The tolerogenic activity of IDO1 has been reported both as a consequence of IDO1 expression by leukemia/lymphoma cells and by an increased IDO1 activity in the tumor microenvironment. The immunosuppressive role of IDO has been recently investigated for the induction of graft tolerance, including allogeneic stem cell transplantation (SCT), which represents a fundamental therapeutic strategy in the management of most hematological malignancies. In this context, some recent reports have indicated IDO1 as a critical regulator of graft-versus-host disease (GVHD). Aim of this chapter is to summarize the most significant and recent advances in the field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (France)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 117.69
Price includes VAT (France)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
EUR 158.24
Price includes VAT (France)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
EUR 158.24
Price includes VAT (France)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

IDO1:

Indoleamine 2,3-dioxygenase 1

AML:

Acute myeloid leukemia

SCT:

Stem cell transplantation

GVHD:

Graft-versus-host disease

HSCs:

Hematopoietic stem cells

1-MT:

1-Methyl tryptophan

COX-2:

Cyclooxygenase-2

CR:

Complete remission

IFN-γ:

Interferon-γ

HGF:

Hepatocyte growth factor

DC:

Dendritic cells

APC:

Antigen-presenting cell

CTLA-4:

T-lymphocyte-associated antigen 4

pDCs:

Plasmacytoid DCs

LDH:

Lactate dehydrogenase

MM:

Multiple myeloma

MSCs:

Mesenchymal stem cells

GVL:

Graft versus leukemia

References

  1. Ayala F, Dewar R, Kieran M, Kalluri R. Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia. 2009;23:2233–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009;113:6215–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Konopleva MY, Jordan CT. Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol. 2011;29:591–9.

    Article  PubMed  Google Scholar 

  4. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.

    Article  CAS  PubMed  Google Scholar 

  5. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20:469–73.

    Article  CAS  PubMed  Google Scholar 

  6. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Grohmann U, Fallarino F, Puccetti P. Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol. 2003;24:242–8.

    Article  CAS  PubMed  Google Scholar 

  8. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762–74.

    Article  CAS  PubMed  Google Scholar 

  9. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269–74.

    Article  CAS  PubMed  Google Scholar 

  10. Curti A, Aluigi M, Pandolfi S, Ferri E, Isidori A, Salvestrini V, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia. 2007;21:353–5.

    Article  CAS  PubMed  Google Scholar 

  11. Munn DH, Mellor AL. IDO and tolerance to tumors. Trends Mol Med. 2004;1:15–8.

    Article  Google Scholar 

  12. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;21:5435–40.

    Article  Google Scholar 

  13. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011;22:6985–91.

    Article  Google Scholar 

  14. Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood. 2009;11:2394–401.

    Article  Google Scholar 

  15. Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood. 2007;7:2871–7.

    Google Scholar 

  16. Curti A, Trabanelli S, Onofri C, Aluigi M, Salvestrini V, Ocadlikova D, et al. Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. Haematologica. 2010;12:2022–30.

    Article  Google Scholar 

  17. Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R, et al. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica. 2009;12:1894–8.

    Google Scholar 

  18. Folgiero V, Goffredo BM, Filippini P, Masetti R, Bonanno G, Caruso R, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia. Oncotarget. 2014;8:2052–64.

    Article  Google Scholar 

  19. Bonanno G, Mariotti A, Procoli A, Folgiero V, Natale D, De Rosa L, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med. 2012;10:247.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Orabona C, Puccetti P, Vacca C, Bicciato S, Luchini A, Fallarino F, et al. Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood. 2006;7:2846–54.

    Article  Google Scholar 

  21. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;11:2516–22.

    Google Scholar 

  22. Grohmann U, Bianchi R, Orabona C, Fallarino F, Vacca C, Micheletti A, et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J Immunol. 2003;5:2581–7.

    Article  Google Scholar 

  23. Romani L, Bistoni F, Perruccio K, Montagnoli C, Gaziano R, Bozza S, et al. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood. 2006;7:2265–74.

    Article  Google Scholar 

  24. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol. 2002;11:1097–101.

    Article  Google Scholar 

  25. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;12:1206–12.

    Article  Google Scholar 

  26. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol. 2009;4:2475–83.

    Article  Google Scholar 

  27. Muller AJ, DuHadaway JB, Chang MY, Ramalingam A, Sutanto-Ward E, Boulden J, et al. Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion. Cancer Immunol Immunother. 2010;11:1655–63.

    Article  Google Scholar 

  28. Ling W, Zhang J, Yuan Z, Ren G, Zhang L, Chen X, et al. Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res. 2014;5:1576–87.

    Article  Google Scholar 

  29. Choe JY, Yun JY, Jeon YK, Kim SH, Park G, Huh JR, et al. Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC Cancer. 2014;14:335.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Liu XQ, Lu K, Feng LL, Ding M, Gao JM, Ge XL, et al. Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration. Leuk Lymphoma. 2014;2:405–14.

    Article  Google Scholar 

  31. Pfeifer S, Schreder M, Bolomsky A, Graffi S, Fuchs D, Sahota SS, et al. Induction of indoleamine-2,3 dioxygenase in bone marrow stromal cells inhibits myeloma cell growth. J Cancer Res Clin Oncol. 2012;11:1821–30.

    Article  Google Scholar 

  32. Laurence JM, Wang C, Park ET, Buchanan A, Clouston A, Allen RD, et al. Blocking indoleamine dioxygenase activity early after rat liver transplantation prevents long-term survival but does not cause acute rejection. Transplantation. 2008;9:1357–61.

    Article  Google Scholar 

  33. Guillonneau C, Hill M, Hubert FX, Chiffoleau E, Hervé C, Li XL, et al. CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest. 2007;4:1096–106.

    Article  Google Scholar 

  34. Cook CH, Bickerstaff AA, Wang JJ, Nadasdy T, Della Pelle P, Colvin RB, et al. Spontaneous renal allograft acceptance associated with “regulatory” dendritic cells and IDO. J Immunol. 2008;5:3103–12.

    Article  Google Scholar 

  35. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Taylor PA, Mellor AL, Munn DH, et al. Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Blood. 2008;6:3257–65.

    Article  Google Scholar 

  36. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;9624:1579–86.

    Article  Google Scholar 

  37. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;12:4619–21.

    Article  Google Scholar 

  38. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, Mellor AL, Munn DH, Blazar BR. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood. 2009;24:5062–70.

    Article  Google Scholar 

  39. Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E, et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest. 2008;7:2562–5273.

    Google Scholar 

  40. Lu Y, Giver CR, Sharma A, Li JM, Darlak KA, Owens LM, et al. IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity. Blood. 2012;4:1075–85.

    Article  Google Scholar 

Download references

Acknowledgments

The research was supported by the Italian Ministry of Health; Regione Emilia-Romagna (Progetto di Ricerca Università-Regione Emilia-Romagna, 2007–2009, No 1412); Italian Association Against Leukemia, Section of Bologna (BolognAIL); Cassa di Risparmio in Bologna; and Fondazione Fatro.

Author information

Authors and Affiliations

  1. Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, S.Orsola-Malpighi Hospital, Via Massarenti, 9, 40138, Bologna, Italy

    Sarah Parisi & Antonio Curti M.D., Ph.D.

Authors
  1. Sarah Parisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Curti M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Curti M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Parisi, S., Curti, A. (2015). Role of Kynurenine Pathway in Hematological Malignancies. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_23

Download citation

Publish with us

Policies and ethics

Search

Navigation