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Cancer Immunology, Immunotherapy

, Volume 56, Issue 5, pp 641–648 | Cite as

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

  • François GhiringhelliEmail author
  • Cedric Menard
  • Pierre Emmanuel Puig
  • Sylvain Ladoire
  • Stephan Roux
  • François Martin
  • Eric Solary
  • Axel Le Cesne
  • Laurence Zitvogel
  • Bruno Chauffert
Original Article

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.

Keywords

Cyclophosphamide Regulatory T cell Metronomic treatment Immunotherapy 

Notes

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.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • François Ghiringhelli
    • 1
    • 2
    • 3
    • 4
    Email author
  • Cedric Menard
    • 3
  • Pierre Emmanuel Puig
    • 1
  • Sylvain Ladoire
    • 2
  • Stephan Roux
    • 3
  • François Martin
    • 1
  • Eric Solary
    • 1
  • Axel Le Cesne
    • 4
  • Laurence Zitvogel
    • 3
  • Bruno Chauffert
    • 1
    • 2
  1. 1.Unité INSERM 517, Faculté de MédecineDijonFrance
  2. 2.Centre de Lutte contre le CancerDijonFrance
  3. 3.ERM-0208 INSERM, Institut Gustave RoussyVillejuif, Faculté de Médecine Kremlin BicêtreParisFrance
  4. 4.Department of Medicine, Institut Gustave RoussyVillejuif, Faculté de Médecine Kremlin BicêtreParisFrance

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