title: Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death.
abstract: High hydrostatic pressure (HHP) promotes key characteristics of immunogenic cell death (ICD), in thus far resembling immunogenic chemotherapy and ionizing irradiation. Here, we demonstrate that cancer cells succumbing to HHP induce CD4+and CD8+T cell-dependent protective immunityin vivo. Moreover, we show that cell death induction by HHP relies on the overproduction of reactive oxygen species (ROS), causing rapid establishment of the integrated stress response, eIF2α phosphorylation by PERK, and sequential caspase-2, -8 and -3 activation. Non-phosphorylatable eIF2α, depletion of PERK, caspase-2 or -8 compromised calreticulin exposure by cancer cells succumbing to HHP but could not inhibit death. Interestingly, the phagocytosis of HHP-treated malignant cells by dendritic cells was suppressed by the knockdown of caspase-2 in the former. Thus, caspase-2 mediates a key function in the interaction between dying cancer cells and antigen presenting cells. Our results indicate that the ROS→PERK→eIF2α→caspase-2 signaling pathway is central for the perception of HHP-driven cell death as immunogenic.
authors.affiliation: Sotio, Prague, Czech Republic; 2nd Medical Faculty and University Hospital Motol, Charles University, Prague, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Moserova
authors.affiliation: Sotio, Prague, Czech Republic; 2nd Medical Faculty and University Hospital Motol, Charles University, Prague, Czech Republic.
authors.forename: Iva
authors.initials: I
authors.lastname: Truxova
authors.affiliation: Cell Death Research and Therapy Unit, Department of Cellular and Molecular Medicine, KU Leuven University of Leuven , Leuven, Belgium.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology, Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tomala
authors.affiliation: Cell Death Research and Therapy Unit, Department of Cellular and Molecular Medicine, KU Leuven University of Leuven , Leuven, Belgium.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892 , Nantes, France.
authors.forename: Pierre Francois
authors.initials: PF
authors.lastname: Cartron
authors.affiliation: Sotio , Prague, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Vosahlikova
authors.affiliation: Laboratory of Tumor Immunology, Institute of Microbiology, Academy of Sciences of the Czech Republic , Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Kovar
authors.affiliation: Sotio, Prague, Czech Republic; 2nd Medical Faculty and University Hospital Motol, Charles University, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Spisek
authors.affiliation: Sotio, Prague, Czech Republic; 2nd Medical Faculty and University Hospital Motol, Charles University, Prague, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Fucikova
keywords: Caspases; ER stress; ecto-CALR; high hydrostatic pressure; immunogenic cell death