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GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity

Cancer research (Chicago, Ill.), 2017-10, Vol.77 (20), p.5664-5675 [Peer Reviewed Journal]

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research, Inc. Oct 15, 2017 ;ISSN: 0008-5472 ;ISSN: 1538-7445 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-17-0799 ;PMID: 28790065

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Title:
GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity
Author: Cichocki, Frank ; Valamehr, Bahram ; Bjordahl, Ryan ; Zhang, Bin ; Rezner, Betsy ; Rogers, Paul ; Gaidarova, Svetlana ; Moreno, Stacey ; Tuininga, Katie ; Dougherty, Phillip ; McCullar, Valarie ; Howard, Peter ; Sarhan, Dhifaf ; Taras, Emily ; Schlums, Heinrich ; Abbot, Stewart ; Shoemaker, Daniel ; Bryceson, Yenan T ; Blazar, Bruce R ; Wolchko, Scott ; Cooley, Sarah ; Miller, Jeffrey S
Subjects: A549 Cells ; Adoptive transfer ; Animals ; Antibody-Dependent Cell Cytotoxicity - drug effects ; Antitumor activity ; Cancer ; CD57 antigen ; Cell Line, Tumor ; Cell proliferation ; Cell recognition ; Cell surface ; Cellular manufacture ; Conditioning ; Cytotoxicity ; Enzyme Inhibitors - pharmacology ; Female ; Glycogen Synthase Kinase 3 - antagonists & inhibitors ; Glycogen Synthase Kinase 3 - immunology ; Humans ; Immunosurveillance ; Immunotherapy ; Immunotherapy, Adoptive - methods ; Inhibition ; Interleukin 1 ; Interleukin 15 ; Interleukin-15 - pharmacology ; K562 Cells ; Killer Cells, Natural - drug effects ; Killer Cells, Natural - enzymology ; Killer Cells, Natural - immunology ; Kinases ; Malignancy ; Maturation ; Medicin och hälsovetenskap ; Mice ; Mice, Inbred NOD ; Natural killer cells ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - therapy ; Peripheral blood ; Pyridines - pharmacology ; Pyrimidines - pharmacology ; Target recognition ; Toxicity ; Transcription factors ; Tumor necrosis factor ; Viability ; Xenograft Model Antitumor Assays ; Xenografts ; γ-Interferon
Is Part Of: Cancer research (Chicago, Ill.), 2017-10, Vol.77 (20), p.5664-5675
Description: Maturation of human natural killer (NK) cells as defined by accumulation of cell-surface expression of CD57 is associated with increased cytotoxic character and TNF and IFNγ production upon target-cell recognition. Notably, multiple studies point to a unique role for CD57 NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacologic inhibition of GSK3 kinase in peripheral blood NK cells expanded with IL15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK-cell maturation including T-BET, ZEB2, and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFNγ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity. In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy. .
Publisher: United States: American Association for Cancer Research, Inc
Language: English
Identifier: ISSN: 0008-5472
ISSN: 1538-7445
EISSN: 1538-7445
DOI: 10.1158/0008-5472.CAN-17-0799
PMID: 28790065
Source: MEDLINE
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GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research, Inc. Oct 15, 2017 ;ISSN: 0008-5472 ;ISSN: 1538-7445 ;EISSN: 1538-7445 ;DOI: 10.1158/0008-5472.CAN-17-0799 ;PMID: 28790065

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