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Published on: January 6, 2014
Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients
Annelies W Turksma1, Hetty J Bontkes, Janneke J Ruizendaal
1Department of Pathology, VU University Medical Center-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
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.
Insights
Survivin-specific T cells were detected ex vivo and induced in vitro for head and neck cancer (HNSCC) immunotherapy. However, prolonged maintenance of these T cells was unsuccessful, suggesting survivin may not be an ideal immunotherapy target.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Head and neck squamous cell carcinoma (HNSCC) requires novel treatment strategies.
- Survivin is crucial for tumor cell survival and proliferation, making it a potential immunotherapy target.
- This study investigated the presence and induction of survivin-specific T cells.
Purpose of the Study:
- To detect survivin-specific T cells ex vivo in patients with cancer.
- To induce and maintain survivin-specific T cells in vitro using dendritic cells.
- To evaluate survivin as a potential target for HNSCC immunotherapy.
Main Methods:
- Tetramer staining and ELIspot assays were used for T cell detection.
- Autologous dendritic cells were electroporated with survivin mRNA and cytokines (IL21 or IL12).
- Western blotting and immunohistochemistry confirmed protein expression; flow cytometry assessed T cell populations.
Main Results:
- Survivin-specific T cells were detected ex vivo in HNSCC and breast cancer patients.
- In vitro induction of survivin-specific T cells was achieved using engineered dendritic cells.
- Prolonged maintenance of isolated or cloned survivin-specific T cells proved unsuccessful.
- Activated T cells expressed survivin, potentially leading to fratricide.
Conclusions:
- Survivin-specific T cells can be detected and induced in vitro.
- Enforced survivin expression in dendritic cells can stimulate T cells.
- The inability to maintain T cells in vitro suggests survivin may not be optimal for HNSCC immunotherapy due to potential T cell fratricide.
- Further research is needed to identify suitable tumor antigens for HNSCC immunotherapy.
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