Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice
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
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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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 9

After i.t. virus infection, vigorous tumor inflammation due to Treg depletion leads to compensatory induction of MDSCs that inhibits the effect of DC vaccination.

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After i.t. virus infection, vigorous tumor inflammation due to Treg depl...
(A) Treg-depleted, KLN205 tumor–bearing DEREG mice received hTert-Ad i.t. Untreated animals, Treg-depleted animals without viral infection, and hTert-Ad–treated animals without Treg depletion were included as controls. Tumor-infiltrating lymphocytes were isolated and identified by FACS analysis by CD45.2 expression. These cells were gated on CD11b and Gr1. Shown are representative density plots of CD11b+ cells and quantification (n = 4 per group, 2 independent experiments). (B) To determine whether MDSCs are responsible for suppression of antitumor immunity by ODC, CD11b+Gr1hiLy6G+ MDSCs were isolated from virus-treated and Treg-depleted donors and adoptively transferred in recipient mice 1 day prior to application of DCs in the context of ODC. Treated mice without adoptive transfer served as positive control (n = 5 per group, 3 independent experiments). (C) Serum samples of mice were analyzed for virus-specific Abs (IgG and IgM isotypes) by ELISA. *P ≤ 0.05; **P < 0.01.