The angiogenic growth factor and biomarker midkine is a tumor-shared antigen.
The angiogenic factor Midkine (MDK) is overexpressed in various human malignant tumors, although its expression is low or undetectable in normal adult tissues. Its expression in tumors and its detection in plasma have been associated with poor disease outcome, whereas its blockade was found to contribute to tumor regression. By weekly stimulation of T lymphocytes harvested in HLA-A2 healthy donors, we derived CD8 T cell lines specific for several MDK peptides. The T cell response was mostly dominated by two nonamer peptides localized in the signal peptide and in the C-terminal part of the protein, as assessed by IFN-gamma ELISPOT and HLA-A2 tetramer labeling. Peptide-specific T cell lines recognized cells transfected with an MDK-encoded plasmid and tumor cell lines naturally expressing the MDK protein, but not untransfected cells. T cell presentation of the two MDK epitopes was found to be TAP dependent. Experiments performed in HLA-A2 transgenic mice demonstrated the capacity of the two identified CD8 T cell epitopes to elicit a cytotoxic response. Altogether, our data show that the secreted MDK protein is a candidate vaccine for multiple cancers.
Commissariat à l'Energie Atomique-Saclay, Institut de Biologie et Technologies, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.
Jerome
J
Kerzerho
Olivier
O
Adotevi
Florence A
FA
Castelli
Magalie
M
Dosset
Karine
K
Bernardeau
Natacha
N
Szely
Francois
F
Lang
Eric
E
Tartour
Bernard
B
Maillere
D000328:Adult; D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D000078792:Midkine; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D042501:Angiogenic Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C066254:MDK protein, human; D009414:Nerve Growth Factors; D000078792:Midkine