Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism

The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activ...

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Bibliographic Details
Published in:JCI insight 2019-09, Vol.4 (18)
Main Authors: Hamaidia, Malik, Gazon, Hélène, Hoyos, Clotilde, Hoffmann, Gabriela Brunsting, Louis, Renaud, Duysinx, Bernard, Willems, Luc
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Immunological - pharmacology
Antineoplastic Agents, Immunological - therapeutic use
Cancer immunotherapy
Cardiovascular & respiratory systems
Cell Biology
Cell Communication - immunology
Cell Culture Techniques
Cell Line, Tumor - transplantation
Coculture Techniques
Disease Models, Animal
Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein - genetics
Enhancer of Zeste Homolog 2 Protein - immunology
Enhancer of Zeste Homolog 2 Protein - metabolism
Epigenetics
Human health sciences
Humans
Immunogenic Cell Death - drug effects
Immunogenic Cell Death - genetics
Immunology
Lung Neoplasms - immunology
Lung Neoplasms - therapy
Macrophages
Macrophages - immunology
Macrophages - metabolism
Macrophages - transplantation
Male
Mesothelioma - immunology
Mesothelioma - therapy
Mesothelioma, Malignant
Mice
Peroxynitrous Acid - metabolism
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Programmed Cell Death 1 Receptor - immunology
RAW 264.7 Cells - transplantation
Reactive Oxygen Species - metabolism
RNA, Small Interfering - metabolism
Sciences de la santé humaine
Systèmes cardiovasculaire & respiratoire
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Summary:The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27-specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.128474