Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice
Norman Woller, … , Stefan Kubicka, Florian Kühnel
Norman Woller, … , Stefan Kubicka, Florian Kühnel
Published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2570-2582. https://doi.org/10.1172/JCI45585.
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Research Article Oncology

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

Norman Woller, Sarah Knocke, Bettina Mundt, Engin Gürlevik, Nina Strüver, Arnold Kloos, Bita Boozari, Peter Schache, Michael P. Manns, Nisar P. Malek, Tim Sparwasser, Lars Zender, Thomas C. Wirth, Stefan Kubicka, Florian Kühnel

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Figure 5

Application of TLR ligands i.t. cannot replace i.t. virus-induced inflammation as a prerequisite for efficient TAA cross-presentation and effective DC vaccination.

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Application of TLR ligands i.t. cannot replace i.t. virus-induced inflam...
(A) s.c. CMT-OVA tumors were treated with LPS, poly(I:C), or CpG (see Methods) or with 1 × 109 pfu hTert-Ad or rdAd i.t. 3 days after treatment, and CD45+ cells were prepared from tumor tissue. Cross-presentation of TAAs on APCs was investigated in the CD11c+ subpopulation by staining with Ab against SIINFEKL bound to H-2Kb. Maternal CMT64 tumors (lacking OVA expression) infected with hTert-Ad and untreated CMT-OVA tumors served as controls. Shown are representative density plots with the quantification gate for OVA cross-presenting APCs and quantification (n = 3 per group, 2 independent experiments). (B) TLR ligands were tested as adjuvants by i.t. injection to support subsequent DC vaccination and were compared with ODC. The experiment was carried out in the CMT-OVA and KLN-HA models. Model antigen-specific T cell responses were analyzed by ELISpot (n = 4 per group, 3 independent experiments). (C) T cell responses after i.t. application of TLR ligands and DC vaccination in the KLN-HA model were additionally investigated by in vivo cytotoxicity assays. Shown are representative histograms and quantitative evaluation (n = 4 per group, 2 independent experiments). *P ≤ 0.05; **P < 0.01; ***P < 0.001.