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 8

Potent cytotoxic immune response against TAA after ODC depends on the presence of Tregs.

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Potent cytotoxic immune response against TAA after ODC depends on the pr...
(A) KLN-HA tumor–bearing mice received i.t. virus twice over 3 days. Tregs were depleted by CD25-depleting Abs i.v. 2 days prior to each treatment. 2 weeks later, mice were sacrificed, and splenocytes were prepared and subjected to ELISpot analysis of virus- and tumor-specific immune responses (n = 4 per group). (B) Mice received hTert-Ad i.t. and HA-pulsed DC vaccination on day 3, and were Treg depleted by CD25 Ab. i.t. virus or Treg depletion only were additional controls. 14 days after the first treatment, splenocytes were subjected to ELISpot analysis of HA-specific response (n = 5 per group, 2 independent experiments). (C) Experiment in B was repeated in DEREG mice using DT to deplete Tregs. (D) In vivo cytotoxicity assay of the induced antitumoral immune response. Mice were treated as in Figure 7B, with or without DT. Shown are representative histograms (left peak, lacZ-pulsed cells; right peak, HA-pulsed cells) and quantification of cytotoxicity (n = 5 per group, 3 independent experiments). (E) KLN-HA tumors and lung colonies were established in DEREG mice as in Figure 7B, and ODC was done. Groups received DT as indicated. After 3 weeks, lungs were inspected for lung colonies (representative images of 5 per group, experiment repeated twice). Tumor area in lung tissue sections was also determined as in Figure 7B. (F and G) Serum samples of mice from B and C were analyzed for virus-specific Abs by ELISA (IgG and IgM isotypes). *P ≤ 0.05; **P < 0.01.