Skip to main content

Advertisement

Springer Nature Link
Log in

The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14+HLA-DR−/low MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8+ T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

atRA:

All-trans retinoic acid

CML:

Chronic myeloid leukemia

Cox-2:

Cyclo-oxygenase-2

es. ph.:

Established phase

Gr-1high :

CD11b+Ly-6G+Ly-6Clow

Gr-1low :

CD11b+Ly-6G−Ly-6Chigh

HSC:

Hepatic stellate cell

in. ph.:

Induction phase

LPS:

Lipopolysaccharides

MDSC:

Myeloid derived suppressor cell

MoDC:

Monocyte derived dendritic cell

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death 1

TKI:

Tyrosine kinase inhibitor

References

  1. De Veirman K, Van Valckenborgh E, Lahmar Q, Geeraerts X, De Bruyne E, Menu E, Van Riet I, Vanderkerken K, Van Ginderachter JA (2014) Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol 4:349. doi:10.3389/fonc.2014.00349

    Article  PubMed  PubMed Central  Google Scholar 

  2. Diaz-Montero CM, Finke J, Montero AJ (2014) Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin Oncol 41:174–184. doi:10.1053/j.seminoncol.2014.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Escors D, Liechtenstein T, Perez-Janices N et al (2013) Assessing T-cell responses in anticancer immunotherapy: dendritic cells or myeloid-derived suppressor cells? Oncoimmunology 2:e26148. doi:10.4161/onci.26148

    Article  PubMed  PubMed Central  Google Scholar 

  4. Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263. doi:10.1007/s00262-011-1161-9

    Article  CAS  PubMed  Google Scholar 

  5. Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 11:802–807. doi:10.1016/j.intimp.2011.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Medina-Echeverz J, Aranda F, Berraondo P (2014) Myeloid-derived cells are key targets of tumor immunotherapy. Oncoimmunology 3:e28398. doi:10.4161/onci.28398

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68:2561–2563. doi:10.1158/0008-5472.CAN-07-6229

    Article  CAS  PubMed  Google Scholar 

  8. Nagaraj S, Gabrilovich DI (2010) Myeloid-derived suppressor cells in human cancer. Cancer J 16:348–353. doi:10.1097/PPO.0b013e3181eb3358

    Article  CAS  PubMed  Google Scholar 

  9. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V (2014) Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 1319:47–65. doi:10.1111/nyas.12469

    Article  CAS  PubMed  Google Scholar 

  10. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. doi:10.1038/nri2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nagaraj S, Gabrilovich DI (2007) Myeloid-derived suppressor cells. Adv Exp Med Biol 601:213–223

    Article  PubMed  Google Scholar 

  12. Talmadge JE (2007) Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 13:5243–5248. doi:10.1158/1078-0432.CCR-07-0182

    Article  CAS  PubMed  Google Scholar 

  13. Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T, Epstein AL (2011) Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med 9:90. doi:10.1186/1479-5876-9-90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, Bronte V (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244. doi:10.1016/j.coi.2010.01.021

    Article  CAS  PubMed  Google Scholar 

  15. Wesolowski R, Markowitz J, Carson WE 3rd (2013) Myeloid derived suppressor cells-a new therapeutic target in the treatment of cancer. J Immunother Cancer 1:10. doi:10.1186/2051-1426-1-10

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hochst B, Schildberg FA, Sauerborn P et al (2013) Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol 59:528–535. doi:10.1016/j.jhep.2013.04.033

    Article  CAS  PubMed  Google Scholar 

  17. Held SA, Heine A, Mayer KT, Kapelle M, Wolf DG, Brossart P (2013) Advances in immunotherapy of chronic myeloid leukemia CML. Curr Cancer Drug Targets 13:768–774

    Article  CAS  PubMed  Google Scholar 

  18. Jabbour E, Cortes J, Kantarjian H (2011) Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. Cancer 117:897–906. doi:10.1002/cncr.25656

    Article  PubMed  PubMed Central  Google Scholar 

  19. Appel S, Boehmler AM, Grunebach F et al (2004) Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103:538–544. doi:10.1182/blood-2003-03-0975

    Article  CAS  PubMed  Google Scholar 

  20. Ozao-Choy J, Ma G, Kao J et al (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514–2522. doi:10.1158/0008-5472.CAN-08-4709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schade AE, Schieven GL, Townsend R, Jankowska AM, Susulic V, Zhang R, Szpurka H, Maciejewski JP (2008) Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 111:1366–1377. doi:10.1182/blood-2007-04-084814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P (2013) The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 122:1192–1202. doi:10.1182/blood-2013-03-484642

    Article  CAS  PubMed  Google Scholar 

  23. Heine A, Held SA, Daecke SN, Riethausen K, Kotthoff P, Flores C, Kurts C, Brossart P (2015) The VEGF-receptor inhibitor axitinib impairs dendritic cell phenotype and function. PLoS One 10:e0128897. doi:10.1371/journal.pone.0128897

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77:12–19. doi:10.1016/j.critrevonc.2010.02.004

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lowe DB, Bose A, Taylor JL, Tawbi H, Lin Y, Kirkwood JM, Storkus WJ (2014) Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology 3:e27589. doi:10.4161/onci.27589

    Article  PubMed  PubMed Central  Google Scholar 

  26. Motoshima T, Komohara Y, Horlad H et al (2015) Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells. Oncol Rep 33:2947–2953. doi:10.3892/or.2015.3893

    PubMed  Google Scholar 

  27. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553–1560. doi:10.1158/0008-5472.CAN-08-1921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ardeshna KM, Pizzey AR, Devereux S, Khwaja A (2000) The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells. Blood 96:1039–1046

    CAS  PubMed  Google Scholar 

  29. Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, Weinschenk T, Singh-Jasuja H, Brossart P (2008) Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood 111:5610–5620. doi:10.1182/blood-2007-02-075945

    Article  CAS  PubMed  Google Scholar 

  30. Yu Q, Kovacs C, Yue FY, Ostrowski MA (2004) The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8+ T cell memory responses. J Immunol 172:6047–6056

    Article  CAS  PubMed  Google Scholar 

  31. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D (2013) Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother 62:909–918. doi:10.1007/s00262-013-1396-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Obermajer N, Wong JL, Edwards RP, Odunsi K, Moysich K, Kalinski P (2012) PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol Invest 41:635–657. doi:10.3109/08820139.2012.695417

    Article  CAS  PubMed  Google Scholar 

  33. Li RJ, Liu L, Gao W, Song XZ, Bai XJ, Li ZF (2014) Cyclooxygenase-2 blockade inhibits accumulation and function of myeloid-derived suppressor cells and restores T cell response after traumatic stress. J Huazhong Univ Sci Technol Med Sci 34:234–240. doi:10.1007/s11596-014-1264-6

    Article  PubMed  Google Scholar 

  34. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI (2007) Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67:11021–11028. doi:10.1158/0008-5472.CAN-07-2593

    Article  CAS  PubMed  Google Scholar 

  35. Heine A, Held SA, Bringmann A, Holderried TA, Brossart P (2011) Immunomodulatory effects of anti-angiogenic drugs. Leukemia 25:899–905. doi:10.1038/leu.2011.24

    Article  CAS  PubMed  Google Scholar 

  36. Bailey A, McDermott DF (2013) Immune checkpoint inhibitors as novel targets for renal cell carcinoma therapeutics. Cancer J 19:348–352. doi:10.1097/PPO.0b013e31829e3153

    Article  CAS  PubMed  Google Scholar 

  37. McDermott DF, Drake CG, Sznol M et al (2015) Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 33:2013–2020. doi:10.1200/JCO.2014.58.1041

    Article  CAS  PubMed  Google Scholar 

  38. Motzer RJ, Rini BI, McDermott DF et al (2015) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II Trial. J Clin Oncol 33:1430–1437. doi:10.1200/JCO.2014.59.0703

    Article  CAS  PubMed  Google Scholar 

  39. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, Rini B, Finke JH, Cohen PA (2010) Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res 70:3526–3536. doi:10.1158/0008-5472.CAN-09-3278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ko JS, Zea AH, Rini BI et al (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15:2148–2157. doi:10.1158/1078-0432.CCR-08-1332

    Article  CAS  PubMed  Google Scholar 

  41. van Cruijsen H, van der Veldt AA, Vroling L et al (2008) Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin Cancer Res 14:5884–5892. doi:10.1158/1078-0432.CCR-08-0656

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Kati Riethausen, Solveig Daecke and Daniel Schätzlein for the excellent technical support. This study was supported by a grant from BONFOR Forschungsförderung (Annkristin Heine & Bastian Höchst).

Author information

Authors and Affiliations

  1. Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

    Annkristin Heine, Stefanie Andrea Erika Held & Peter Brossart

  2. Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

    Judith Schilling, Percy Knolle & Bastian Höchst

  3. Institute for Pathology, University Hospital Bonn, Bonn, Germany

    Heidrun Gevensleben

  4. Institute of Experimental Immunology, University Bonn, Bonn, Germany

    Annkristin Heine, Natalio Garbi & Christian Kurts

  5. Institute for Molecular Immunology and Experimental Oncology, Technische Universität München, Munich, Germany

    Barbara Grünwald, Achim Krüger, Percy Knolle & Bastian Höchst

  6. Institute of Experimental Immunology and Hepatology, University Hamburg Eppendorf, Hamburg, Germany

    Linda Diehl

Authors
  1. Annkristin Heine
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Judith Schilling
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Barbara Grünwald
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Achim Krüger
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Heidrun Gevensleben
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Stefanie Andrea Erika Held
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Natalio Garbi
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Christian Kurts
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Peter Brossart
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Percy Knolle
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Linda Diehl
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Bastian Höchst
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Annkristin Heine or Bastian Höchst.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 91176 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heine, A., Schilling, J., Grünwald, B. et al. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother 65, 273–282 (2016). https://doi.org/10.1007/s00262-015-1790-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-015-1790-5

Keywords