title: Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice.
abstract: Vaccination using DCs pulsed with tumor lysates or specific tumor-associated peptides has so far yielded limited clinical success for cancer treatment, due mainly to the low immunogenicity of tumor-associated antigens. In this study, we have identified intratumoral virus-induced inflammation as a precondition for effective antitumor DC vaccination in mice. Administration of a tumor-targeted DC vaccine during ongoing virus-induced tumor inflammation, a regimen referred to as oncolysis-assisted DC vaccination (ODC), elicited potent antitumoral CD8+ T cell responses. This potent effect was not replicated by TLR activation outside the context of viral infection. ODC-elicited immune responses mediated marked tumor regression and successful eradication of preestablished lung colonies, an essential prerequisite for potentially treating metastatic cancers. Unexpectedly, depletion of Tregs during ODC did not enhance therapeutic efficacy; rather, it abrogated antitumor cytotoxicity. This phenomenon could be attributed to a compensatory induction of myeloid-derived suppressor cells in Treg-depleted and thus vigorously inflamed tumors, which prevented ODC-mediated immune responses. Consequently, Tregs are not only general suppressors of immune responses, but are essential for the therapeutic success of multimodal and temporally fine-adjusted vaccination strategies. Our results highlight tumor-targeting, replication-competent viruses as attractive tools for eliciting effective antitumor responses upon DC vaccination.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Woller
authors.forename: Sarah
authors.initials: S
authors.lastname: Knocke
authors.forename: Bettina
authors.initials: B
authors.lastname: Mundt
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.forename: Nina
authors.initials: N
authors.lastname: Strüver
authors.forename: Arnold
authors.initials: A
authors.lastname: Kloos
authors.forename: Bita
authors.initials: B
authors.lastname: Boozari
authors.forename: Peter
authors.initials: P
authors.lastname: Schache
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wirth
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014780:Viruses / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines