The inhibition of TNF-alpha anti-tumoral properties by blocking antibodies promotes tumor growth in a rat model.
Tumor necrosis factor (TNF) antagonists represent a milestone in the therapy of autoimmune conditions. Anti-TNF antibodies have been approved for clinical use and during the last eight years thousands of patients have been treated. However, the long-term sequelae of anti-TNF agents in promoting carcinogenesis remain unclear. This study sought to define the role of intra-tumor TNF-alpha production on cancer cell progression and to determine whether TNF-alpha antibodies can suppress anti-tumoral immunity. Using an experimental animal tumor model we demonstrate that anti-TNF-alpha antibodies hinder anti-tumor immune responses and promote growth of immunogenic rat colon tumors (REG) that are always rejected by immunocompetent untreated rats. The major role of TNF-alpha in the anti-tumoral immune response was confirmed by transfecting progressive and tolerogenic rat colon tumor cells (PRO) with the TNF-alpha gene. PRO tumor cells secreting TNF-alpha induce tumor-infiltrating dendritic cell (DC) activation. This triggers a potent immune response leading to tumor rejection and long-lasting immunity. Therefore, the prominent role of TNF-alpha in anti-tumoral immune responses underscores the need for caution and close surveillance following the administration of TNF inhibitors.
Larmonier
Nicolas
N
INSERM U517, IFR 100, Faculty of Medicine, Dijon, France.
Cathelin
Dominique
D
Larmonier
Claire
C
Nicolas
Alexandra
A
Merino
Delphine
D
Janikashvili
Nona
N
Audia
Sylvain
S
Bateman
Andrew
A
Thompson
Jill
J
Kottke
Tim
T
Hartung
Thomas
T
Katsanis
Emmanuel
E
Vile
Richard
R
Bonnotte
Bernard
B
D000818:Animals; D019138:Antibodies, Blocking / Q000009:adverse effects* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D009389:Neovascularization, Pathologic / Q000276:immunology; D051381:Rats; D011923:Rats, Nude; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D019138:Antibodies, Blocking; D014409:Tumor Necrosis Factor-alpha