title: IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells.
abstract: 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.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden;
authors.forename: Vincent
authors.initials: V
authors.lastname: van Hoef
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden;
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY; and.
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden;
authors.forename: Julie
authors.initials: J
authors.lastname: Lorent
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Kristina
authors.initials: K
authors.lastname: Witt
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden;
authors.forename: Laia
authors.initials: L
authors.lastname: Masvidal
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden;
authors.forename: Shuo
authors.identifier: 0000-0002-5574-1645
authors.initials: S
authors.lastname: Liang
authors.affiliation: Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL.
authors.forename: Shannon
authors.initials: S
authors.lastname: Murray
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden;
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL.
authors.forename: Andreas
authors.identifier: 0000-0002-9709-2970
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D019409:Interleukin-15; D024101:Mitochondrial Proteins; D058570:TOR Serine-Threonine Kinases