Abstract:
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Khawam K,Giron-Michel J,Gu Y,Perier A,Giuliani M,Caignard A,Devocelle A,Ferrini S,Fabbi M,Charpentier B,Ludwig A,Chouaib S,Azzarone B,Eid Pdoi
10.1158/0008-5472.CAN-08-3198subject
Has Abstractpub_date
2009-02-15 00:00:00pages
1561-9issue
4eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-08-3198journal_volume
69pub_type
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