Idelalisib Rescues Natural Killer Cells from Monocyte-Induced Immunosuppression by Inhibiting NOX2-Derived Reactive Oxygen Species
| Autor: | Roberta Kiffin, Ebru Aydin, Olle Werlenius, Kristoffer Hellstrand, Ali A. Akhiani, Alexander Hallner, Johan Aurelius, Anna Martner, Fredrik B. Thorén |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Myeloid Chronic lymphocytic leukemia Immunology Melanoma Experimental Antineoplastic Agents Monocytes 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Neoplasm Metastasis Phosphoinositide-3 Kinase Inhibitors Quinazolinones Immunosuppression Therapy Mice Knockout NADPH oxidase biology Chemistry Monocyte medicine.disease Antigens CD20 Leukemia Lymphocytic Chronic B-Cell Killer Cells Natural Mice Inbred C57BL Leukemia 030104 developmental biology medicine.anatomical_structure Apoptosis Purines 030220 oncology & carcinogenesis NADPH Oxidase 2 biology.protein Cancer research Idelalisib Reactive Oxygen Species |
| Zdroj: | Cancer immunology research. 8(12) |
| ISSN: | 2326-6074 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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