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Cancer Immunology Research
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Idelalisib Rescues Natural Killer Cells from Monocyte-Induced Immunosuppression by Inhibiting NOX2-Derived Reactive Oxygen Species

Ali A. Akhiani, Alexander Hallner, Roberta Kiffin, Ebru Aydin, Olle Werlenius, Johan Aurelius, Anna Martner, Fredrik B. Thorén and Kristoffer Hellstrand
Ali A. Akhiani
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Alexander Hallner
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
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Roberta Kiffin
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
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Ebru Aydin
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
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  • ORCID record for Ebru Aydin
Olle Werlenius
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
3Department of Hematology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Johan Aurelius
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
3Department of Hematology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Anna Martner
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
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Fredrik B. Thorén
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
4Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Kristoffer Hellstrand
1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2TIMM Laboratory, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
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  • For correspondence: kristoffer.hellstrand@microbio.gu.se
DOI: 10.1158/2326-6066.CIR-20-0055 Published December 2020
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Abstract

The phosphatidylinositol-4,5-bisphosphate-3 kinase-δ (PI3Kδ) inhibitor idelalisib, used alone or in combination with anti-CD20, is clinically efficacious in B-cell lymphoma and chronic lymphocytic leukemia (CLL) by promoting apoptosis of malignant B cells. PI3K regulates the formation of reactive oxygen species (ROS) by the myeloid NADPH oxidase NOX2, but the role of PI3Kδ in myeloid cell–induced immunosuppression is unexplored. We assessed the effects of idelalisib on the spontaneous and IgG antibody–induced ROS production by human monocytes, on ROS-induced cell death of human natural killer (NK) cells, and on tumor cell clearance in an NK cell–dependent mouse model of metastasis. Idelalisib potently and efficiently inhibited the formation of NOX2-derived ROS from monocytes and rescued NK cells from ROS-induced cell death. Idelalisib also promoted NK cell cytotoxicity against anti–CD20-coated primary human CLL cells and cultured malignant B cells. Experiments using multiple PI3K inhibitors implicated the PI3Kδ isoform in regulating NOX2-induced ROS formation and immunosuppression. In B6 mice, systemic treatment with idelalisib significantly reduced the formation of lung metastases from intravenously injected melanoma cells but did not affect metastasis in B6.129S6-Cybbtm1Din (Nox2−/−) mice or in NK cell–deficient mice. Our results imply that idelalisib rescues NK cells from NOX2/ROS-dependent immunosuppression and thus exerts antineoplastic efficacy beyond B-cell inhibition.

Footnotes

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

  • Cancer Immunol Res 2020;8:1532–41

  • Received January 30, 2020.
  • Revision received June 24, 2020.
  • Accepted September 16, 2020.
  • Published first September 23, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (12)
December 2020
Volume 8, Issue 12
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Idelalisib Rescues Natural Killer Cells from Monocyte-Induced Immunosuppression by Inhibiting NOX2-Derived Reactive Oxygen Species
Ali A. Akhiani, Alexander Hallner, Roberta Kiffin, Ebru Aydin, Olle Werlenius, Johan Aurelius, Anna Martner, Fredrik B. Thorén and Kristoffer Hellstrand
Cancer Immunol Res December 1 2020 (8) (12) 1532-1541; DOI: 10.1158/2326-6066.CIR-20-0055

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Idelalisib Rescues Natural Killer Cells from Monocyte-Induced Immunosuppression by Inhibiting NOX2-Derived Reactive Oxygen Species
Ali A. Akhiani, Alexander Hallner, Roberta Kiffin, Ebru Aydin, Olle Werlenius, Johan Aurelius, Anna Martner, Fredrik B. Thorén and Kristoffer Hellstrand
Cancer Immunol Res December 1 2020 (8) (12) 1532-1541; DOI: 10.1158/2326-6066.CIR-20-0055
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