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Microenvironment and Immunology

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

Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart Abbot, Daniel Shoemaker, Yenan T. Bryceson, Bruce R. Blazar, Scott Wolchko, Sarah Cooley and Jeffrey S. Miller
Frank Cichocki
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Bahram Valamehr
Fate Therapeutics Inc., San Diego, California.
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Ryan Bjordahl
Fate Therapeutics Inc., San Diego, California.
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Bin Zhang
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Betsy Rezner
Fate Therapeutics Inc., San Diego, California.
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Paul Rogers
Fate Therapeutics Inc., San Diego, California.
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Svetlana Gaidarova
Fate Therapeutics Inc., San Diego, California.
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Stacey Moreno
Fate Therapeutics Inc., San Diego, California.
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Katie Tuininga
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Phillip Dougherty
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Valarie McCullar
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Peter Howard
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Dhifaf Sarhan
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Emily Taras
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Heinrich Schlums
Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Stewart Abbot
Fate Therapeutics Inc., San Diego, California.
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Daniel Shoemaker
Fate Therapeutics Inc., San Diego, California.
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Yenan T. Bryceson
Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Bruce R. Blazar
Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Scott Wolchko
Fate Therapeutics Inc., San Diego, California.
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Sarah Cooley
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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Jeffrey S. Miller
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota.
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  • For correspondence: mille011@umn.edu
DOI: 10.1158/0008-5472.CAN-17-0799 Published October 2017
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Abstract

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 ex vivo 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 ex vivo 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. Cancer Res; 77(20); 5664–75. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received March 18, 2017.
  • Revision received May 31, 2017.
  • Accepted August 3, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (20)
October 2017
Volume 77, Issue 20
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GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity
Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart Abbot, Daniel Shoemaker, Yenan T. Bryceson, Bruce R. Blazar, Scott Wolchko, Sarah Cooley and Jeffrey S. Miller
Cancer Res October 15 2017 (77) (20) 5664-5675; DOI: 10.1158/0008-5472.CAN-17-0799

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GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity
Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart Abbot, Daniel Shoemaker, Yenan T. Bryceson, Bruce R. Blazar, Scott Wolchko, Sarah Cooley and Jeffrey S. Miller
Cancer Res October 15 2017 (77) (20) 5664-5675; DOI: 10.1158/0008-5472.CAN-17-0799
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