title: Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis.
abstract: The crucial issue for defining successful natural killer (NK)-based anticancer therapy is the ability of tumor cells to activate resistance mechanisms leading to escape from NK-mediated killing. It is now well established that such mechanisms are likely evolved under hypoxia in the tumor microenvironment. Here, we show that hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and might pave the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors.
authors.affiliation: Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
authors.forename: Elodie
authors.initials: E
authors.lastname: Viry
authors.affiliation: Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
authors.forename: Joanna
authors.initials: J
authors.lastname: Baginska
authors.affiliation: Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.affiliation: INSERM U753; Institut de Cancérologie Gustave Roussy; Villejuif, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Medves
authors.affiliation: INSERM U753; Institut de Cancérologie Gustave Roussy; Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: Laboratory of Experimental Hemato-Oncology; Department of Oncology; Public Research Center for Health; Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
mesh_terms: D000818:Animals; D001343:Autophagy; D015687:Cell Hypoxia; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D059748:Proteolysis
chemical_list: D053804:Granzymes
keywords: autophagy; breast cancer; granzyme B; hypoxia; natural killer