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Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression.
Unger, Wendy Wj Mayer, Christian T Engels, Steef Hesse, Christina Perdicchio, Maurizio Puttur, Franz Streng-Ouwehand, Ingeborg Litjens, Manja Kalay, Hakan Berod, Luciana
Unger, Wendy Wj
Mayer, Christian T
Engels, Steef
Hesse, Christina
Perdicchio, Maurizio
Puttur, Franz
Streng-Ouwehand, Ingeborg
Litjens, Manja
Kalay, Hakan
Berod, Luciana
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2015-08
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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 by Foxp3(+) 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 transient Foxp3(+) 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.
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Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression. 2015, 4 (8):e970462 Oncoimmunology
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2162-4011