title: Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress.
abstract: In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2α phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca(2+)-ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.
authors.affiliation: INSERM, U848, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, Villejuif, Val de Marne F-94805, France. kroemer@orange.fr
authors.forename: I
authors.initials: I
authors.lastname: Martins
authors.forename: O
authors.initials: O
authors.lastname: Kepp
authors.forename: F
authors.initials: F
authors.lastname: Schlemmer
authors.forename: S
authors.initials: S
authors.lastname: Adjemian
authors.forename: M
authors.initials: M
authors.lastname: Tailler
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: M
authors.initials: M
authors.lastname: Michaud
authors.forename: L
authors.initials: L
authors.lastname: Menger
authors.forename: A
authors.initials: A
authors.lastname: Gdoura
authors.forename: N
authors.initials: N
authors.lastname: Tajeddine
authors.forename: A
authors.initials: A
authors.lastname: Tesniere
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064032:Calbindin 2; D045744:Cell Line, Tumor; D002469:Cell Separation; D002945:Cisplatin / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D021381:Protein Transport / Q000187:drug effects; D064030:S100 Calcium Binding Protein G / Q000276:immunology / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D064032:Calbindin 2; D009944:Organoplatinum Compounds; D064030:S100 Calcium Binding Protein G; D000077150:Oxaliplatin; D019284:Thapsigargin; D002945:Cisplatin