Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes.
We determined the number and functional status of CD4+ CD25(high) regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9.2% of CD4+ T cells) compared to 24 healthy donors (7.1%). These cells expressed the transcription factor forkhead box P3 (FoxP3), glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) and intracellular CD152, and demonstrated a suppressive activity in vitro against CD4+ CD25- autologous proliferation. At a single intravenous infusion, cyclophosphamide failed, in association with a non-specific immunotherapy by intratumoral bacille Calmette-Guérin (BCG), to modulate significantly Treg numbers or function. Metastatic cancer is associated with an expansion of peripheral blood CD4+ CD25(high) FoxP3+ GITR+ CD152+ Treg cells whose immunosuppressive properties do not differ from those of healthy subjects. Moreover, cyclophosphamide administration may not represent an optimal therapy to eliminate Treg, which further underlines the need to identify specific agents that would selectively deplete these cells.
Audia
S
S
INSERM, UMR 866, Faculty of Medicine and Pharmacy, Hospital du Bocage, Dijon, France.
Nicolas
A
A
Cathelin
D
D
Larmonier
N
N
Ferrand
C
C
Foucher
P
P
Fanton
A
A
Bergoin
E
E
Maynadie
M
M
Arnould
L
L
Bateman
A
A
Lorcerie
B
B
Solary
E
E
Chauffert
B
B
Bonnotte
B
B
D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D018906:Antineoplastic Agents, Alkylating; D001500:BCG Vaccine; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens