PMID- 27465917
OWN - NLM
STAT- MEDLINE
DCOM- 20170731
LR  - 20220311
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 128
IP  - 11
DP  - 2016 Sep 15
TI  - IL-15 activates mTOR and primes stress-activated gene expression leading to 
      prolonged antitumor capacity of NK cells.
PG  - 1475-89
LID - 10.1182/blood-2016-02-698027 [doi]
AB  - 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.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Mao, Yumeng
AU  - Mao Y
AD  - Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, Sweden;
FAU - van Hoef, Vincent
AU  - van Hoef V
AD  - Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, 
      Sweden;
FAU - Zhang, Xiaonan
AU  - Zhang X
AD  - Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Medical and 
      Health Sciences, Linkoping University, Linkoping, Sweden;
FAU - Wennerberg, Erik
AU  - Wennerberg E
AD  - 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.
FAU - Lorent, Julie
AU  - Lorent J
AD  - Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, 
      Sweden;
FAU - Witt, Kristina
AU  - Witt K
AD  - Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, Sweden;
FAU - Masvidal, Laia
AU  - Masvidal L
AD  - Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, 
      Sweden;
FAU - Liang, Shuo
AU  - Liang S
AUID- ORCID: 0000-0002-5574-1645
AD  - Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, 
      Sweden;
FAU - Murray, Shannon
AU  - Murray S
AD  - Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL.
FAU - Larsson, Ola
AU  - Larsson O
AD  - Department of Oncology-Pathology, Karolinska Institutet, SciLifeLab, Solna, 
      Sweden;
FAU - Kiessling, Rolf
AU  - Kiessling R
AD  - Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, Sweden;
FAU - Lundqvist, Andreas
AU  - Lundqvist A
AUID- ORCID: 0000-0002-9709-2970
AD  - Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, Sweden; Cell Therapy Institute, Nova 
      Southeastern University, Fort Lauderdale, FL.
LA  - eng
PT  - Journal Article
DEP - 20160727
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-15)
RN  - 0 (Mitochondrial Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins/genetics
MH  - Cytokines/metabolism
MH  - Cytotoxicity, Immunologic/*immunology
MH  - Humans
MH  - *Immunotherapy, Adoptive
MH  - Interleukin-15/*pharmacology
MH  - Killer Cells, Natural/*immunology/metabolism/pathology
MH  - Lymphocyte Activation
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Mitochondrial Proteins/genetics
MH  - Neoplasms, Experimental/immunology/pathology/*therapy
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC5025899
EDAT- 2016/07/29 06:00
MHDA- 2017/08/02 06:00
PMCR- 2016/09/15
CRDT- 2016/07/29 06:00
PHST- 2016/02/11 00:00 [received]
PHST- 2016/07/13 00:00 [accepted]
PHST- 2016/07/29 06:00 [entrez]
PHST- 2016/07/29 06:00 [pubmed]
PHST- 2017/08/02 06:00 [medline]
PHST- 2016/09/15 00:00 [pmc-release]
AID - S0006-4971(20)34138-0 [pii]
AID - 2016/698027 [pii]
AID - 10.1182/blood-2016-02-698027 [doi]
PST - ppublish
SO  - Blood. 2016 Sep 15;128(11):1475-89. doi: 10.1182/blood-2016-02-698027. Epub 2016 
      Jul 27.