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.
Highlights
Interleukin-15 (IL-15) is a proinflammatory cytokine that plays an important role in both the innate and adaptive immune system
We and others have previously shown that renal cancer cells (RCC) do no secrete detectable amount of free IL-15 [23, 28] but express a mb-IL-15 not anchored through the IL-15Ra chain [24]
Reverse transcription–PCR (RT-PCR) analysis strengthens flow cytometry data showing that RCC cell lines (HIEG and ACHN), primary cultures of healthy renal tissue, primary tumor and metastasis derived from the same patient (RCC5-N, RCC5-T, RCC5Met), and primary tumor RCC7 cells and virus transformed epithelial embryonic kidney cells (HK2) only express the 536 transcript coding for the secretable IL-15 form [29]
Summary
Interleukin-15 (IL-15) is a proinflammatory cytokine that plays an important role in both the innate and adaptive immune system. IL-15 promotes the activation of neutrophils and macrophages and is critical to dendritic cell function. IL-15 is essential to the development, homeostasis, function, and survival of natural killer (NK) cells, NK T cells, and memory CD8+ T cells. Based on these properties, IL-15 has been proposed as a useful cytokine for immunotherapy [1]. IL-15 production by human melanoma, colon cancer, or prostate cancer cells contributes to the progression of the disease [7,8,9,10,11,12]
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