title: Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response.
abstract: Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy.
authors.affiliation: Équipe Contrôle Métabolique des Morts Cellulaires and Équipe Mort Cellulaire, Différenciation et Cancer, Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire, 06204 Nice, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bénéteau
authors.forename: Barbara
authors.initials: B
authors.lastname: Zunino
authors.forename: Marie A
authors.initials: MA
authors.lastname: Jacquin
authors.forename: Ophélie
authors.initials: O
authors.lastname: Meynet
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Ludivine A
authors.initials: LA
authors.lastname: Pradelli
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchetti
authors.forename: Aurore
authors.initials: A
authors.lastname: Cornille
authors.forename: Michel
authors.initials: M
authors.lastname: Carles
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D037282:Calreticulin / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034622:RNA Interference; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D037282:Calreticulin; D005047:Etoposide; D003847:Deoxyglucose