Cancer Immunology, Immunotherapy

, Volume 61, Issue 2, pp 193–202 | Cite as

The immune inhibitory receptor osteoactivin is upregulated in monocyte-derived dendritic cells by BCR–ABL tyrosine kinase inhibitors

  • Mark-Alexander Schwarzbich
  • Michael Gutknecht
  • Julia Salih
  • Helmut R. Salih
  • Peter Brossart
  • Susanne M. Rittig
  • Frank Grünebach
Original article

Abstract

Multiple approaches presently aim to combine targeted therapies using tyrosine kinase inhibitors with immunotherapy. Ex vivo-generated dendritic cells are frequently used in such strategies due to their unique ability to initiate primary T-cell immune responses. Besides governing tumor cell growth, many kinases targeted by tyrosine kinase inhibitors are involved in the development and function of dendritic cells and thus tyrosine kinase inhibitor therapy may cause immunoinhibitory side effects. We here report that exposure of developing human monocyte-derived dendritic cells to the BCR–ABL inhibitors imatinib, dasatinib, and nilotinib results in profound upregulation of the transmembrane glycoprotein osteoactivin that has recently been characterized as a negative regulator of T-cell activation. Thus, in line with osteoactivin upregulation, exposure to tyrosine kinase inhibitors resulted in significantly reduced stimulatory capacity of dendritic cells in mixed lymphocyte reactions that could be restored by the addition of blocking anti-osteoactivin antibody. Our data demonstrate that tyrosine kinase inhibitor-mediated inhibition of dendritic cell function is, at least in great part, mediated by upregulation of the immune inhibitory molecule osteoactivin.

Keywords

Dendritic cells Immunotherapy Tyrosine kinase inhibitors Immune inhibitory receptor 

Notes

Acknowledgments

This work was supported by Deutsche Krebshilfe (project no. 109046) and SFB 685. S. M. Rittig is supported by the European Social Fund in Baden-Württemberg. We thank Sylvia Stephan for excellent technical assistance.

Supplementary material

262_2011_1096_MOESM1_ESM.pdf (107 kb)
Supplementary material 1 (PDF 106 kb)

References

  1. 1.
    Shawver LK, Slamon D, Ullrich A (2002) Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1:117–123PubMedCrossRefGoogle Scholar
  2. 2.
    Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ et al (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56:100–104PubMedGoogle Scholar
  3. 3.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566PubMedCrossRefGoogle Scholar
  4. 4.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedCrossRefGoogle Scholar
  5. 5.
    de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S et al (2007) Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 109:1408–1413PubMedCrossRefGoogle Scholar
  6. 6.
    Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23:1054–1061PubMedCrossRefGoogle Scholar
  7. 7.
    Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270PubMedCrossRefGoogle Scholar
  8. 8.
    Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259PubMedCrossRefGoogle Scholar
  9. 9.
    Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F et al (2010) Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116:3852–3861PubMedCrossRefGoogle Scholar
  10. 10.
    Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029–1035PubMedCrossRefGoogle Scholar
  11. 11.
    Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al (2003) Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101:4701–4707PubMedCrossRefGoogle Scholar
  12. 12.
    Melief CJM (2008) Cancer immunotherapy by dendritic cells. Immunity 29:372–383PubMedCrossRefGoogle Scholar
  13. 13.
    Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258PubMedCrossRefGoogle Scholar
  14. 14.
    Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9:271–296PubMedCrossRefGoogle Scholar
  15. 15.
    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384PubMedCrossRefGoogle Scholar
  16. 16.
    Appel S, Boehmler AM, Grünebach F, Müller MR, Rupf A, Weck MM et al (2004) Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103:538–544PubMedCrossRefGoogle Scholar
  17. 17.
    Appel S, Rupf A, Weck MM, Schoor O, Brümmendorf TH, Weinschenk T et al (2005) Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-kappaB and Akt signaling pathways. Clin Cancer Res 11:1928–1940PubMedCrossRefGoogle Scholar
  18. 18.
    Brauer KM, Werth D, von Schwarzenberg K, Bringmann A, Kanz L, Grünebach F et al (2007) BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells. Cancer Res 67:5489–5497PubMedCrossRefGoogle Scholar
  19. 19.
    Safadi FF, Xu J, Smock SL, Rico MC, Owen TA, Popoff SN (2002) Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts. J Cell Biochem 84:12–26CrossRefGoogle Scholar
  20. 20.
    Chung JS, Sato K, Dougherty II, Cruz PD Jr, Ariizumi K (2007) DC-HIL is a negative regulator of T lymphocyte activation. Blood 109:4320–4327PubMedCrossRefGoogle Scholar
  21. 21.
    Chung JS, Bonkobara M, Tomihari M, Cruz PA, Ariizumi K (2009) The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. Eur J Immunol 39:965–974PubMedCrossRefGoogle Scholar
  22. 22.
    Shikano S, Bonkobara M, Zukas PK, Ariizumi K (2001) Molecular cloning of a dendritic cell-associated transmembrane protein, DC-HIL, that promotes RGD-dependent adhesion of endothelial cells through recognition of heparan sulfate proteoglycans. J Biol Chem 276:8125–8134PubMedCrossRefGoogle Scholar
  23. 23.
    Chung JS, Dougherty I, Cruz PD, Ariizumi K (2007) Syndecan-4 mediates the coinhibitory function of DC-HIL on T cell activation. J Immunol 179:5778–5784PubMedGoogle Scholar
  24. 24.
    Knödler A, Schmidt SM, Bringmann A, Weck MM, Brauer KM, Holderried TA et al (2009) Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. Leukemia 23:535–544PubMedCrossRefGoogle Scholar
  25. 25.
    Brossart P, Grünebach F, Stuhler G, Reichardt VL, Möhle R, Kanz L et al (1998) Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor. Blood 92:4238–4247PubMedGoogle Scholar
  26. 26.
    Brossart P, Schneider A, Dill P, Schammann T, Grünebach F, Wirths S et al (2001) The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res 61:6846–6850PubMedGoogle Scholar
  27. 27.
    Neumann F, Herold C, Hildebrandt B, Kobbe G, Aivado M, Rong A et al (2003) Quantitative real-time reverse-transcription polymerase chain reaction for diagnosis of BCR-ABL positive leukemias and molecular monitoring following allogeneic stem cell transplantation. Eur J Haematol 70:1–10PubMedCrossRefGoogle Scholar
  28. 28.
    Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145PubMedGoogle Scholar
  29. 29.
    Hantschel O, Rix U, Superti-Furga G (2008) Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leukemia Lymphoma 49:615–619PubMedCrossRefGoogle Scholar
  30. 30.
    O’Hare T, Walters DK, Stoffregen EP, Jia TP, Manley PW, Mestan J et al (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500–4505PubMedCrossRefGoogle Scholar
  31. 31.
    Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B et al (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551PubMedCrossRefGoogle Scholar
  32. 32.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401PubMedCrossRefGoogle Scholar
  33. 33.
    Li JN, Rix U, Fang B, Bai Y, Edwards A, Colinge J et al (2010) A chemical and phosphoproteomic characterization of dasatinib action in lung cancer. Nat Chem Biol 6:291–299PubMedCrossRefGoogle Scholar
  34. 34.
    Brossart P, Zobywalski A, Grünebach F, Behnke L, Stuhler G, Reichardt VL et al (2000) Tumor necrosis factor alpha and CD40 ligand antagonize the inhibitory effects of interleukin 10 on T-cell stimulatory capacity of dendritic cells. Cancer Res 60:4485–4492PubMedGoogle Scholar
  35. 35.
    Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L et al (1998) IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol 28:359–369PubMedCrossRefGoogle Scholar
  36. 36.
    Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH (1997) Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780PubMedGoogle Scholar
  37. 37.
    Nicholson GC, Malakellis M, Collier FM, Cameron PU, Holloway WR, Gough TJ et al (2000) Induction of osteoclasts from CD14-positive human peripheral blood mononuclear cells by receptor activator of nuclear factor kappa B ligand (RANKL). Clin Sci 99:133–140PubMedCrossRefGoogle Scholar
  38. 38.
    Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825PubMedCrossRefGoogle Scholar
  39. 39.
    Kariko K, Bhuyan P, Capodici J, Ni HP, Lubinski J, Friedman H et al (2004) Exogenous siRNA mediates sequence-independent gene suppression by signaling through Toll-like receptor 3. Cells Tissues Organs 177:132–138PubMedCrossRefGoogle Scholar
  40. 40.
    Kariko K, Bhuyan P, Capodici J, Weissman D (2004) Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol 172:6545–6549PubMedGoogle Scholar
  41. 41.
    Riley JK, Takeda K, Akira S, Schreiber RD (1999) Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem 274:16513–16521PubMedCrossRefGoogle Scholar
  42. 42.
    Eklund KK, Lindstedt K, Sandler C, Kovanen PT, Laasonen L, Juurikivi A et al (2008) Maintained efficacy of the tyrosine kinase inhibitor imatinib mesylate in a patient with rheumatoid arthritis. JCR J Clin Rheumatol 14:294–296CrossRefGoogle Scholar
  43. 43.
    Swanson CD, Paniagua RT, Lindstrom TM, Robinson WH (2009) Tyrosine kinases as targets for the treatment of rheumatoid arthritis. Nat Rev Rheumatol 5:317–324CrossRefGoogle Scholar
  44. 44.
    Tebib J, Mariette X, Bourgeois P, Flipo RM, Gaudin P, Le Loet X et al (2009) Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study. Arthr Res Ther 11:R95CrossRefGoogle Scholar
  45. 45.
    Tristano AG (2009) Tyrosine kinases as targets in rheumatoid arthritis. Int Immunopharmacol 9:1–9PubMedCrossRefGoogle Scholar
  46. 46.
    Vernon MR, Pearson L, Atallah E (2009) Resolution of rheumatoid arthritis symptoms with imatinib mesylate. JCR J Clin Rheumatol 15:267CrossRefGoogle Scholar
  47. 47.
    Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Mark-Alexander Schwarzbich
    • 1
  • Michael Gutknecht
    • 1
  • Julia Salih
    • 1
  • Helmut R. Salih
    • 1
  • Peter Brossart
    • 2
  • Susanne M. Rittig
    • 1
  • Frank Grünebach
    • 1
  1. 1.Department of Oncology, Hematology, Immunology, Rheumatology and PulmologyUniversity of TübingenTübingenGermany
  2. 2.Department of Hematology and OncologyUniversity of BonnBonnGermany

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