Title |
IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
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Published in |
Blood, July 2016
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DOI | 10.1182/blood-2016-02-698027 |
Pubmed ID | |
Authors |
Yumeng Mao, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Andreas Lundqvist |
Abstract |
Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor post-infusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK cell functions following cytokine withdrawal to model post-infusion performance. In contrasts 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 mRNA revealed 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 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 67% |
Science communicators (journalists, bloggers, editors) | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United Kingdom | 1 | <1% |
Unknown | 135 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 35 | 26% |
Researcher | 28 | 21% |
Student > Bachelor | 16 | 12% |
Student > Master | 13 | 10% |
Student > Doctoral Student | 10 | 7% |
Other | 12 | 9% |
Unknown | 22 | 16% |
Readers by discipline | Count | As % |
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Immunology and Microbiology | 41 | 30% |
Biochemistry, Genetics and Molecular Biology | 27 | 20% |
Agricultural and Biological Sciences | 16 | 12% |
Medicine and Dentistry | 14 | 10% |
Engineering | 3 | 2% |
Other | 9 | 7% |
Unknown | 26 | 19% |