Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells.
Survivin, a member of the inhibitor of apoptosis protein family, is expressed in almost all types of malignancies, making this protein a useful tool for the development of broadly applicable vaccination therapies. We used a recently identified HLA-A2 binding peptide and dendritic cells (DCs) from healthy donors to induce survivin-specific cytotoxic T lymphocytes (CTLs) in vitro. These T cells efficiently lysed target cells pulsed with the cognate peptide. Furthermore, survivin-specific CTLs recognized HLA-A2-matched tumor cell lines and primary malignant cells from patients with leukemia in an antigen-specific and HLA-restricted manner as demonstrated with the use of cold target inhibition assays and blocking antibodies. To validate the immunogenicity of survivin we performed the experiments in an autologous setting and used monocyte-derived DCs as targets. Interestingly, we found that DCs up-regulate survivin expression on stimulation with tumor necrosis factor alpha (TNF-alpha). However, these mature DCs were not recognized by survivin-specific CTLs, whereas they lysed autologous mature DCs pulsed with the antigenic peptide or transfected with whole tumor RNA purified from a survivin-expressing cell line. To further analyze the possible use of survivin-specific CTLs in cancer therapies, we induced survivin-specific CTLs using peripheral blood mononuclear cells (PBMNCs) and DCs from a patient with chronic lymphocytic leukemia (CLL). The in vitro-generated T cells efficiently recognized autologous malignant CLL cells, whereas they spared autologous-purified nonmalignant B cells or DCs. Our results demonstrate that survivin epitopes are presented on a broad variety of malignancies and can be applied in vaccination therapies.
Schmidt
Susanne M
SM
Department of Hematology, Oncology and Immunology, University of Tübingen, Germany.
Schag
Kerstin
K
Müller
Martin R
MR
Weck
Markus M
MM
Appel
Silke
S
Kanz
Lothar
L
Grünebach
Frank
F
Brossart
Peter
P
D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007938:Leukemia / Q000276:immunology; D008164:Luminescent Proteins / Q000235:genetics; D008213:Lymphocyte Activation; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins