Skip to main content

Advertisement

SpringerLink
Log in

Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy

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

Abstract

Recent studies have suggested that dendritic cell (DC)-based immunotherapy is one promising approach for the treatment of cancer. We previously studied the clinical toxicity, feasibility, and efficacy of cancer vaccine therapy with peptide-pulsed DCs. In that study, we used granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood monocytes as a cell source of DCs. However, previous investigations have suggested that G-CSF-mobilized peripheral blood monocytes produce reduced levels of proinflammatory cytokines such as interleukin (IL)-12 and tumor necrosis factor (TNF)-α. These T helper (Th)-1-type cytokines are thought to promote antitumor immune response. In this study, we assessed the functional abilities of DCs generated from G-CSF-mobilized monocytes obtained from 13 patients with CEA-positive advanced solid cancers. Peripheral blood mononuclear cells were obtained from leukapheresis products collected before and after systemic administration of G-CSF (subcutaneous administration of high-dose [5–10 μg/kg] human recombinant G-CSF for five consecutive days). In vitro cytokine production profiles after stimulation with lipopolysaccharide (LPS) were compared between monocytes with and without G-CSF mobilization. DCs generated from monocytes were also examined with respect to cytokine production and the capacity to induce peptide-specific T cell responses. Administration of G-CSF was found to efficiently mobilize peripheral blood monocytes. Although G-CSF-mobilized monocytes (G/Mo) less effectively produced Th-1-type cytokines than control monocytes (C/Mo), DCs generated from G/Mo restored the same level of IL-12 production as that seen in DCs generated from C/Mo. T cell induction assay using recall antigen peptide and phenotypic analyses also demonstrated that DCs generated from G/Mo retained characteristics identical to those generated from C/Mo. Our results suggest that G-CSF mobilization can be used to collect monocytes as a cell source for the generation of DCs for cancer immunotherapy. DCs generated in this fashion were pulsed with HLA-A24-restricted CEA epitope peptide and administered to patients safely; immunological responses were induced in some patients.

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

Access this article

Log in via an institution

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
Fig. 6

Similar content being viewed by others

References

  1. Timmerman JM, Levy R (1999) Dendritic cell vaccines for cancer immunotherapy. Annu Rev Med 50:507

    Article  PubMed  CAS  Google Scholar 

  2. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R et al (1998) Vaccination of melanoma patients with peptide- or tumor lysates-pulsed dendritic cells. Nat Med 4:328

    Article  PubMed  CAS  Google Scholar 

  3. Schuler TB, Schultz ES, Berger TG, Weinlich G, Ebner S, Woerl P et al (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195:1279

    Article  PubMed  CAS  Google Scholar 

  4. Paneli MC, Wunderlich J, Jeffries J, Wang E, Mixon A, Rosenberg SA et al (2000) Phase 1 study in melanoma-associated antigens MART-1 and gp100. J Immunother 23:487

    Article  Google Scholar 

  5. Lau R, Wang F, Jeffery G, Marty V, Kuniyoshi J, Made E et al (2001) Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma. J Immunother 24:66

    Article  PubMed  CAS  Google Scholar 

  6. Murphy GP, Tjoa BA, Simmons SJ, Jarisch J, Bowes VA, Radge H et al (1999) Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease. Prostate 38:73

    Article  PubMed  CAS  Google Scholar 

  7. Horiguchi Y, Nukaya I, Okazawa K, Kawashima I, Fikes J, Sette A et al (2002) Screening of HLA-A24-restricted epitope peptides from prostate-specific membrane antigen that induce specific antitumor cytotoxic T lymphocytes. Clin Cancer Res 8:3885

    PubMed  CAS  Google Scholar 

  8. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA et al (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci USA 98:8809

    Article  PubMed  CAS  Google Scholar 

  9. Sadanaga N, Nagashima H, Mashino K, Tahara K, Yamaguchi H, Ohta M et al (2001) Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas. Clin Cancer Res 7:2277

    PubMed  CAS  Google Scholar 

  10. Ueda Y, Itoh T, Nukaya I, Kawashima I, Okugawa K, Yano Y et al (2004) Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen-derived, HLA-A24-restricted CTL epitope: clinical outcomes of 18 cases with metastatic gastrointestinal or lung adenocarcinomas. Int J Oncol 24:909

    PubMed  CAS  Google Scholar 

  11. McIlroy D, Gregoire M (2003) Optimizing dendritic cell-based anticancer immunotherapy: maturation state does have clinical impact. Cancer Immunol Immunother 52:583

    Article  PubMed  Google Scholar 

  12. Kessinger A, Armitage JO (1991) The evolving role of autologous peripheral stem cell transplantation following high-dose therapy for malignancies. Blood 77:211

    PubMed  CAS  Google Scholar 

  13. Teshima T, Harada M, Takamatsu Y, Makino K, Taniguchi S, Inaba S et al (1992) Cytotoxic drug and cytotoxic drug/G-CSF mobilization of peripheral blood stem cells and their use for autografting. Bone Marrow Transplant 10:215

    PubMed  CAS  Google Scholar 

  14. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 18:175

    Article  Google Scholar 

  15. Saito M, Kiyokawa N, Taguchi T, Suzuki K, Sekino T, Mimori K et al (2002) Granulocyte colony-stimulating factor directly affects human monocytes and modulates cytokine secretion. Exp Hematol 30:1115

    Article  PubMed  CAS  Google Scholar 

  16. Mielcarek M, Graf L, Johnson G, Torok-Storb B (1998) Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation. Blood 92:215

    PubMed  CAS  Google Scholar 

  17. Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T (2000) Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood 95:270

    PubMed  CAS  Google Scholar 

  18. Bensinger WI, Clift RA, Anasetti C, Appelbaum FA, Demirer T, Rowley S et al (1996) Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony stimulating factor. Stem Cells 14:90

    Article  PubMed  CAS  Google Scholar 

  19. Pan L, Delmonte J Jr, Jalen CK, Ferrara JL (1995) Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 86:4422

    PubMed  CAS  Google Scholar 

  20. Sloand EM, Kim S, Maciejewski JP, VanRhee F, Chaurhuri A, Barrett J et al (2000) Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo. Blood 95:2269

    PubMed  CAS  Google Scholar 

  21. Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4, downregulated by tumor necrosis factor alpha. J Exp Med 179:1109–1118

    Article  PubMed  CAS  Google Scholar 

  22. Rutella S, Rumi C, Lucia MB, Sica S, Cauda R, Leone G (1998) Serum of healthy donors receiving granulocyte colony-stimulating factor induces T cell unresponsiveness. Exp Hematol 26:1024

    PubMed  CAS  Google Scholar 

  23. Kalinski P, Mailliard RB, Giermasz A, Zeh HJ, Basse P, Bartlett DL et al (2005) Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther 5:1303

    Article  PubMed  CAS  Google Scholar 

  24. Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54:721

    Article  PubMed  CAS  Google Scholar 

  25. Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaji N (1996) Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods 196:121

    Article  PubMed  CAS  Google Scholar 

  26. Syme RM, Duggan P, Stewart D, Gluck S (2001) Generation of dendritic cells ex vivo: differences in steady state versus mobilized blood from patients with breast cancer, with lymphoma, and from normal donors. J Hematother Stem Cell Res 10:621

    Article  PubMed  CAS  Google Scholar 

  27. Choi D, Perrin M, Hoffmann S, Chang AE, Ratanatharaorn V, Uberti J et al (1998) Dendritic cell-based vaccines in the setting of peripheral blood stem cell transplantation: CD34+ cell-depleted mobilized peripheral blood can serve as a source of potent dendritic cells. Clin Cancer Res 4:2709

    PubMed  CAS  Google Scholar 

  28. Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl KE, Engelman EG et al (1999) Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma—a feasibility study. Blood 93:2411

    PubMed  CAS  Google Scholar 

  29. Mielcarek M, Martin PJ, Torok-Storb B (1997) Suppression of alloantigen-induced T-cell proliferation by CD14+ cells derived from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells. Blood 89:1629

    PubMed  CAS  Google Scholar 

  30. Tanaka J, Mielcarek M, Torok-Storb B (1998) Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD4 T cells. Blood 91:347

    PubMed  CAS  Google Scholar 

  31. Jonuleit H, Giesecke-Tuettenberg A, Tuting T, Thurner-Schuler B, Stuge TB, Paragnik L et al (2001) A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 93:243

    Article  PubMed  CAS  Google Scholar 

  32. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I et al (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39

    Article  PubMed  CAS  Google Scholar 

  33. Ino K, Singh RK, Talmadge JE (1997) Monocytes from mobilized stem cells inhibit T cell function. J Leukoc Biol 61:583–591

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the following Grants-In-Aid for Scientific Research from the Japan Society for the Promotion of Science: no. 13470259 (2001–2003, to H.Y.), no. 14571152 (2002–2003, to Y.U.), no. 16591341 (2004–2005, to N.F.).

Author information

Authors and Affiliations

  1. Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Yuji Ueda, Tsuyoshi Itoh, Nobuaki Fuji, Sachio Harada, Hiroshi Fujiki, Keiji Shimizu, Atsushi Shiozaki, Arihiro Iwamoto, Takeshi Shimizu & Hisakazu Yamagishi

  2. Department of Microbiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Osam Mazda

  3. Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8506, Japan

    Takafumi Kimura & Yoshiaki Sonoda

  4. Department of Hematology and Oncology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Masafumi Taniwaki

Authors
  1. Yuji Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsuyoshi Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuaki Fuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sachio Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Fujiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keiji Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Atsushi Shiozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arihiro Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takeshi Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Osam Mazda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takafumi Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshiaki Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masafumi Taniwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hisakazu Yamagishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Ueda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueda, Y., Itoh, T., Fuji, N. et al. Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy. Cancer Immunol Immunother 56, 381–389 (2007). https://doi.org/10.1007/s00262-006-0197-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0197-8

Keywords

Search

Navigation