Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition.
Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.
Khawam
Krystel
K
Institut National de la Sante et de la Recherche Medicale UMR 542, Université de Paris-Sud, Hôpital Paul Brousse, Villejuif Cedex, France.
Giron-Michel
Julien
J
Gu
Yanhong
Y
Perier
Aurélie
A
Giuliani
Massimo
M
Caignard
Anne
A
Devocelle
Aurore
A
Ferrini
Silvano
S
Fabbi
Marina
M
Charpentier
Bernard
B
Ludwig
Andreas
A
Chouaib
Salem
S
Azzarone
Bruno
B
Eid
Pierre
P
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D019409:Interleukin-15 / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008648:Mesoderm / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000276:immunology; D053647:Receptors, Interleukin-15 / Q000276:immunology*; D019346:Sodium Acetate / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D019346:Sodium Acetate; D013755:Tetradecanoylphorbol Acetate