Open Access Research

Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients

Annelies W Turksma1, Hetty J Bontkes1, Janneke J Ruizendaal1, Kirsten BJ Scholten1, Johanneke Akershoek1, Shakila Rampersad1, Laura M Moesbergen1, Saskia AGM Cillessen1, Saskia JAM Santegoets3, Tanja D de Gruijl3, C René Leemans2, Chris JLM Meijer1 and Erik Hooijberg14*

Author Affiliations

1 Department of Pathology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

2 Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

3 Department of Medical Oncology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

4 VUMC-CCA, (room 2.26), De Boelelaan 1117, NL-1081 HV, Amsterdam, The Netherlands

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Journal of Translational Medicine 2013, 11:152  doi:10.1186/1479-5876-11-152

Published: 20 June 2013

Abstract

Background

New treatment modalities are needed for the treatment of cancers of the head and neck region (HNSCC). Survivin is important for the survival and proliferation of tumor cells and may therefore provide a target for immunotherapy. Here we focused on the ex vivo presence and in vitro induction of survivin specific T cells.

Methods

Tetramer staining and ELIspot assays were used to document the presence of survivin specific T cells in patient derived material, and to monitor the presence and persistence of survivin specific T cells after repeated in vitro stimulation with autologous dendritic cells.

Results

Ex vivo analysis showed the presence of survivin-specific T cells in the peripheral blood (by tetramer analysis) and in the draining lymph node (by ELIspot analysis) in a HNSCC and a locally advanced breast cancer patient respectively. However, we were unable to maintain isolated survivin specific T cells for prolonged periods of time. For the in vitro generation of survivin specific T cells, monocyte derived DC were electroporated with mRNA encoding full length survivin or a survivin mini-gene together with either IL21 or IL12 mRNA. Western blotting and immunohistochemical staining of dendritic cell cytospin preparations confirmed translation of the full length survivin protein. After repeated stimulation we observed an increase, followed by a decrease, of the number of survivin specific T cells. FACS sorted or limiting dilution cloned survivin specific T cells could not be maintained on feeder mix for prolonged periods of time. Protein expression analysis subsequently showed that activated, but not resting T cells contain survivin protein.

Conclusions

Here we have shown that survivin specific T cells can be detected ex vivo in patient derived material. Furthermore, survivin specific T cells can be induced in vitro using autologous dendritic cells with enforced expression of survivin and cytokines. However, we were unable to maintain enriched or cloned survivin specific T cells for prolonged periods of time. Endogenous expression of survivin in activated T cells and subsequent fratricide killing might explain our in vitro observations. We therefore conclude that survivin, although it is a universal tumor antigen, might not be the ideal target for immunotherapeutic strategies for the treatment of cancer of the head and neck.

Keywords:
Immunotherapy; DC based vaccines; HNSCC; Survivin; Messenger RNA; Fratricide