The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer.
Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor alpha (TNFalpha), IL-17, etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble alpha chain of IL-15 receptor (sIL-15Ralpha), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15Ralpha was performed with a newly developed RIA. Increased serum sIL-15Ralpha concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15Ralpha was mainly produced by tumor cells via proteolytic cleavage of IL-15Ralpha mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Ralpha concentrations. Surprisingly, sIL-15Ralpha did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15-induced proinflammatory cytokines (IL-6, TNFalpha, and IL-17) that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15Ralpha. Overall, these results support for the first time an original protumor role of sIL-15Ralpha in cancer.
Badoual
Cécile
C
EA 4054 Université Paris Descartes, Faculté de Medecine; Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
Bouchaud
Grégory
G
Agueznay
Nour El Houda
Nel H
Mortier
Erwan
E
Hans
Stéphane
S
Gey
Alain
A
Fernani
Fahima
F
Peyrard
Séverine
S
-Puig
Pierre Laurent
PL
Bruneval
Patrick
P
Sastre
Xavier
X
Plet
Ariane
A
Garrigue-Antar
Laure
L
Quintin-Colonna
Françoise
F
Fridman
Wolf H
WH
Brasnu
Daniel
D
Jacques
Yannick
Y
Tartour
Eric
E
D051722:ADAM Proteins / Q000096:biosynthesis; D000072198:ADAM17 Protein; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D019409:Interleukin-15 / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000097:blood / Q000737:chemistry / Q000502:physiology*; D008954:Models, Biological; D015999:Multivariate Analysis; D011379:Prognosis; D020033:Protein Isoforms; D011863:Radioimmunoassay
D003432:Cross-Linking Reagents; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D020033:Protein Isoforms; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human