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 1

DC vaccination during viral tumor inflammation elicits a potent and therapeutically efficient antitumor immune response.

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DC vaccination during viral tumor inflammation elicits a potent and ther...
(A) s.c. grown KLN205 tumors in DBA/2 mice were inoculated with i.t. injection of hTert-Ad. Virus-mediated inflammation of tumor tissue was histologically examined on H&E-stained slides at the indicated times. Original magnification, ×100 (low-power) and ×200 (high-power). (B) s.c. grown KLN205 or CMT64 tumors were treated with hTert-Ad (hT-Ad) i.t. and tumor cell lysate–pulsed DCs (DCT), as shown in the schematic. 14 days after initial treatment, splenocytes of mice were harvested, and ELISpot assays were performed after restimulation with tumor cell lysate. Number of tumor-specific splenocytes in a representative experiment is shown as spot-forming units (SFU) per well (n = 5 per group, 4 independent experiments). (C) s.c. grown KLN205 tumors were treated with hTert-Ad i.t. followed by tumor cell lysate–pulsed DCs on day 3 after viral treatment. This treatment was compared with mice receiving 2 subsequent i.t. injections of virus or 2 subsequent DC vaccinations. All treatments were performed on days 0 and 3. Untreated tumor-bearing mice served as control (n = 8 per group, 2 independent experiments). *P ≤ 0.05; ***P < 0.001.