title: Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression.
abstract: Therapeutic vaccinations against cancer are still largely ineffective. Major caveats are inefficient delivery of tumor antigens to dendritic cells (DCs) and excessive immune suppression byFoxp3+regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transientFoxp3+Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8+T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Wendy Wj
authors.initials: WW
authors.lastname: Unger
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hanover and the Helmholtz Centre for Infection Research , Hannover, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Mayer
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Steef
authors.initials: S
authors.lastname: Engels
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hanover and the Helmholtz Centre for Infection Research , Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hesse
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Perdicchio
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hanover and the Helmholtz Centre for Infection Research , Hannover, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Puttur
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Streng-Ouwehand
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Manja
authors.initials: M
authors.lastname: Litjens
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hanover and the Helmholtz Centre for Infection Research , Hannover, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Berod
authors.affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hanover and the Helmholtz Centre for Infection Research , Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Department of Molecular Cell Biology and Immunology; VU University Medical Center ; Amsterdam, The Netherlands ;
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
keywords: DC targeting vaccination; DC-SIGN; melanoma; regulatory T cells; tumor rejection