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Generation of survivin-specific CD8+ T effector cells by dendritic cells pulsed with protein or selected peptides
M Schmitz1, P Diestelkoetter, B Weigle
1Institute for Immunology, Medical Faculty, Technical University of Dresden, Germany.
Abstract:
The identification of tumor-associated antigens recognized by CD8+ cytotoxic T cells paved the way to new concepts in adjuvant anticancer therapy. However, the number of tumor-associated proteins found to be expressed in the majority of human cancers is still rather limited. Recently, the newly identified apoptosis inhibitor protein survivin has been recognized as a widely occurring tumor-associated protein. In the present study, we demonstrate that survivin is capable of inducing specific CD8+ effector T cells in vitro. T cells from healthy donors were subjected to several cycles of stimulation by autologous dendritic cells (DCs) pulsed with soluble recombinant survivin protein. Activation of CD8+ cytotoxic T cells by survivin-derived peptides cross-presented by DCs was demonstrated by lysis of autologous survivin-expressing B cell transfectants. Using a peptide-motif scoring system, two survivin peptides (ELTLGE-FLKL and TLPPAWQPFL) were predicted and proved to bind to the HLA-A*0201 molecule. Both peptides were shown to induce CD8+ effector T cells when presented on DCs; one peptide could be verified to result from natural intracellular processing of survivin. These findings recommend survivin as a new and widely applicable target for protein- and peptide-based immunotherapy of tumors.
Insights
Survivin, a tumor-associated protein, can stimulate CD8+ effector T cells. This discovery highlights survivin as a promising target for novel cancer immunotherapies.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Adjuvant anticancer therapy relies on tumor-associated antigens for CD8+ cytotoxic T cell recognition.
- Limited identification of widely expressed tumor-associated proteins hinders therapeutic development.
- Survivin, an apoptosis inhibitor, is increasingly recognized as a prevalent tumor-associated protein.
Purpose of the Study:
- To investigate survivin's potential to induce specific CD8+ effector T cells.
- To evaluate survivin-derived peptides as targets for T cell-mediated tumor immunotherapy.
Main Methods:
- In vitro stimulation of T cells from healthy donors using autologous dendritic cells (DCs) pulsed with recombinant survivin.
- Assessment of CD8+ cytotoxic T cell activation via lysis of survivin-expressing B cell transfectants.
- Prediction and validation of HLA-A*0201-binding survivin peptides using a peptide-motif scoring system.
Main Results:
- Survivin successfully induced specific CD8+ effector T cells in vitro.
- Two survivin peptides (ELTLGE-FLKL and TLPPAWQPFL) were identified as binders to HLA-A*0201.
- Both validated peptides induced CD8+ effector T cells when presented by DCs; one peptide arose from natural survivin processing.
Conclusions:
- Survivin is a viable target for inducing tumor-specific CD8+ T cell responses.
- Survivin-based protein and peptide immunotherapies offer a broadly applicable strategy for cancer treatment.