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IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
Karolinska Institute, Sweden.
Karolinska Institute, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
Karolinska Institute, Sweden; Weill Cornell Med, NY USA.
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 11, 1475-1489 p.Article in journal (Refereed) Published
Abstract [en]

Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2016. Vol. 128, no 11, 1475-1489 p.
National Category
Cell and Molecular Biology
URN: urn:nbn:se:liu:diva-132538DOI: 10.1182/blood-2016-02-698027ISI: 000385733200006PubMedID: 27465917OAI: diva2:1046371

Funding Agencies|Swedish Cancer Society [CAN 2012/474, CAN 2015/421, CAN 2013/737]; Swedish Childhood Cancer Foundation [PR2014-0093]; Swedish Foundation for International Cooperation in Research and Higher Education [IB2014-5690]; Cancer Research Foundations of Radiumhemmet [141272]; Swedish Research Council [2013-3055]; Wallenberg Academy Fellow Program; Strategic Research Programme in Cancer (STRATCAN)

Available from: 2016-11-14 Created: 2016-11-13 Last updated: 2016-11-14

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Zhang, Xiaonan
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