Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor α chain, epithelial-to-mesenchymal transition

Krystel Khawam, Julien Giron-Michel, Yanhong Gu, Aurélie Perier, Massimo Giuliani, Anne Caignard, Aurore Devocelle, Silvano Ferrini, Marina Fabbi, Bernard Charpentier, Andreas Ludwig, Salem Chouaib, Bruno Azzarone, Pierre Eid

Research output: Contribution to journalArticle

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 α (s-IL-15Rα) 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 (α-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-15Rα subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Rα 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.

Original languageEnglish
Pages (from-to)1561-1569
Number of pages9
JournalCancer Research
Volume69
Issue number4
DOIs
Publication statusPublished - Feb 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    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, P. (2009). Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor α chain, epithelial-to-mesenchymal transition. Cancer Research, 69(4), 1561-1569. https://doi.org/10.1158/0008-5472.CAN-08-3198