Article (Scientific journals)
Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism.
Hamaïdia, Malik; Gazon, Hélène; Hoyos, Clotilde et al.
2019In JCI Insight, 4 (18), p. 128474
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Keywords :
Cancer immunotherapy; Cell Biology; Epigenetics; Immunology; Macrophages
Abstract :
[en] 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.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Hamaïdia, Malik  ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Gazon, Hélène ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Hoyos, Clotilde ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Hoffmann, Gabriela Brunsting
Louis, Renaud ;  Université de Liège - ULiège > Département des sciences cliniques > Pneumologie - Allergologie
Duysinx, Bernard ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Oncologie thoracique
Willems, Luc  ;  Université de Liège - ULiège > Cancer-Cellular and Molecular Epigenetics
Language :
English
Title :
Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism.
Publication date :
2019
Journal title :
JCI Insight
eISSN :
2379-3708
Publisher :
American Society for Clinical Investigation, Ann Harbor, United States - Michigan
Volume :
4
Issue :
18
Pages :
e128474
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 12 November 2019

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