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

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.

• Authors: Ali A Akhiani, Alexander Hallner, Roberta Kiffin, Ebru Aydin, Olle Werlenius, Johan Aurelius, Anna Martner, Fredrik B Thorén, Kristoffer Hellstrand
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 8 Issue 12 Pg. 1532-1541 (12 2020) ISSN: 2326-6074 [Electronic] United States
• PMID: 32967913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antigens, CD20
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Purines
• Quinazolinones
• Reactive Oxygen Species
• Cybb protein, mouse
• NADPH Oxidase 2
• idelalisib

Topics

• Animals
• Antigens, CD20 (immunology)
• Antineoplastic Agents (pharmacology)
• Humans
• Immunosuppression Therapy
• Killer Cells, Natural (immunology)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, immunology, pathology)
• Melanoma, Experimental (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (metabolism)
• NADPH Oxidase 2 (genetics, immunology)
• Neoplasm Metastasis
• Phosphoinositide-3 Kinase Inhibitors
• Purines (pharmacology)
• Quinazolinones (pharmacology)
• Reactive Oxygen Species (metabolism)