Skip to main content

Advertisement

SpringerLink
Log in

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients

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

Abstract

CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as “metronomic” therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

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

Similar content being viewed by others

References

  1. Baecher-Allan C, Wolf E, Hafler DA (2005) Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells. Clin Immunol 115:S10–S18

    Article  Google Scholar 

  2. Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458

    Article  CAS  PubMed  Google Scholar 

  3. Steitz J, Bruck J, Lenz J, Knop J, Tuting T (2001) Depletion of CD25(+) CD4(+) T cells and treatment with tyrosinase-related protein 2-transduced dendritic cells enhance the interferon alpha-induced, CD8(+) T-cell-dependent immune defense of B16 melanoma. Cancer Res 61:8643–8646

    CAS  PubMed  Google Scholar 

  4. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344

    Article  CAS  PubMed  Google Scholar 

  5. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L (2005) Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202:919–929

    Article  CAS  PubMed  Google Scholar 

  6. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH (2001) Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:4766–4772

    CAS  PubMed  Google Scholar 

  7. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    CAS  PubMed  Google Scholar 

  8. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  9. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J Exp Med 202:1075–1085

    Article  CAS  PubMed  Google Scholar 

  10. Awwad M, North RJ (1989) Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res 49:1649–1654

    CAS  PubMed  Google Scholar 

  11. Berd D, Mastrangelo MJ (1987) Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset. Cancer Res 47:3317–3321

    CAS  PubMed  Google Scholar 

  12. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. (2005) Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868

    Article  CAS  PubMed  Google Scholar 

  13. Taieb J, Chaput N, Schartz N, Roux S, Novault S, Menard C, Ghiringhelli F, Terme M, Carpentier AF, Darrasse-Jese G, Lemonnier F, Zitvogel L. (2006) Chemo-immunotherapy of tumors: cyclophosphamide synergizes with exosome-based vaccines. J Immunol 176:2722–2729

    CAS  PubMed  Google Scholar 

  14. Gasparini G (2001) Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2:733–740

    Article  CAS  PubMed  Google Scholar 

  15. Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, Kerbel RS (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061

    Article  CAS  PubMed  Google Scholar 

  16. Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 98:1643–1648

    Article  CAS  PubMed  Google Scholar 

  17. Shaked Y, Emmenegger U, Francia G, Chen L, Lee CR, Man S, Paraghamian A, Ben-David Y, Kerbel RS (2005) Low dose metronomic combined with intermittent bolus cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res 65:7045–7051

    Article  CAS  PubMed  Google Scholar 

  18. Beyer M, Kochanek M, Darabi K, Endl E, Weihrauch MR, Knolle PA, Classen S, Schultze JL (2005) Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukaemia after therapy with fludarabine. Blood 106:2018–2025

    Article  CAS  PubMed  Google Scholar 

  19. Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA (2005) Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 28:582–592

    Article  CAS  PubMed  Google Scholar 

  20. Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V (2003) Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 63:8408–8413

    CAS  PubMed  Google Scholar 

  21. Schiavoni G, Mattei F, Di Pucchio T, Santini SM, Bracci L, Belardelli F, Proietti E (2000) Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood 95:2024–2030

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

FG received a grant from the Ligue Nationale contre le Cancer (Cote d’Or committee). LZ received a grant from EU ALLOSTEM and DC-THERA and ERM0208 was supported by the Ligue Nationale contre le Cancer.

Author information

Authors and Affiliations

  1. Unité INSERM 517, Faculté de Médecine, 7 boulevard Jeanne D’Arc, 21000, Dijon, France

    François Ghiringhelli, Pierre Emmanuel Puig, François Martin, Eric Solary & Bruno Chauffert

  2. Centre de Lutte contre le Cancer, Dijon, France

    François Ghiringhelli, Sylvain Ladoire & Bruno Chauffert

  3. ERM-0208 INSERM, Institut Gustave Roussy, Villejuif, Faculté de Médecine Kremlin Bicêtre, Paris, France

    François Ghiringhelli, Cedric Menard, Stephan Roux & Laurence Zitvogel

  4. Department of Medicine, Institut Gustave Roussy, Villejuif, Faculté de Médecine Kremlin Bicêtre, Paris, France

    François Ghiringhelli & Axel Le Cesne

Authors
  1. François Ghiringhelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cedric Menard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Emmanuel Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvain Ladoire
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephan Roux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. François Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric Solary
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Axel Le Cesne
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Laurence Zitvogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruno Chauffert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to François Ghiringhelli.

Additional information

François Ghiringhelli and Cedric Menard contributed equally to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ghiringhelli, F., Menard, C., Puig, P.E. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56, 641–648 (2007). https://doi.org/10.1007/s00262-006-0225-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0225-8

Keywords

Search

Navigation