title: Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis.
abstract: Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can induce an immunogenic type of cell death stimulating tumor-specific immunity. Here, we show that cyclophosphamide (CTX) exerts two types of actions relevant for the induction of antitumor immunity in vivo: (i) effect on dendritic cell (DC) homeostasis, mediated by endogenous type I interferons (IFN-I), leading to the preferential expansion of CD8α(+) DC, the main subset involved in the cross-presentation of cell-derived antigens; and (ii) induction of tumor cell death with clear-cut immunogenic features capable of stimulating tumor infiltration, engulfment of tumor apoptotic material, and CD8 T-cell cross-priming by CD8α(+) DC. Notably, the antitumor effects of CTX were efficiently amplified by IFN-I, the former providing a source of antigen and a "resetting" of the DC compartment and the latter supplying optimal costimulation for T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. These results disclose new perspectives for the development of targeted and more effective chemoimmunotherapy treatments of cancer patients.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Schiavoni
authors.forename: Antonella
authors.initials: A
authors.lastname: Sistigu
authors.forename: Mara
authors.initials: M
authors.lastname: Valentini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mattei
authors.forename: Paola
authors.initials: P
authors.lastname: Sestili
authors.forename: Francesca
authors.initials: F
authors.lastname: Spadaro
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.forename: Silvia
authors.initials: S
authors.lastname: Lorenzi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: D'Urso
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Gabriele
authors.forename: Enrico
authors.initials: E
authors.lastname: Proietti
authors.forename: Laura
authors.initials: L
authors.lastname: Bracci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004357:Drug Synergism; D007370:Interferon Type I / Q000276:immunology / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D013945:Thymoma / Q000188:drug therapy / Q000276:immunology
chemical_list: D007370:Interferon Type I; D003520:Cyclophosphamide