title: Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
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.
authors.affiliation: Unité INSERM 517, Faculté de Médecine, Dijon, France. francois.ghiringhelli@wanadoo.fr
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Cedric
authors.initials: C
authors.lastname: Menard
authors.forename: Pierre Emmanuel
authors.initials: PE
authors.lastname: Puig
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Stephan
authors.initials: S
authors.lastname: Roux
authors.forename: François
authors.initials: F
authors.lastname: Martin
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D053645:Interleukin-2 Receptor alpha Subunit; D003520:Cyclophosphamide