Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity.
Defined tumor-associated antigens (TAA) are attractive targets for anti-tumor immunotherapy. Here, we describe a novel genome-wide approach to identify multiple TAA from any given tumor. A panel of transplantable thymomas was established from an inbred p53-/- mouse strain. The resulting tumors were examined for gene expression by mRNA microarray scanning. This analysis revealed heterogeneity of the tumors in agreement with the assumption that they represent different tumorigenic events. Several genes were overexpressed in one or more of the tumors. To examine whether overexpressed genes might be used to identify TAA, mice were immunized with mixtures of peptides representing putative cytotoxic T cell epitopes derived from one of the gene products. Indeed, such immunized mice were partially protected against subsequent tumor challenge. Despite being immunized with bona fide self antigens, no clinical signs of autoimmune reactions were observed. Thus, it appears possible to evaluate the entire metabolism of any given tumor and use this information rationally to identify multiple epitopes of value in the generation of tumor-specific immunotherapy. We expect that human tumors express similar tumor-specific metabolic imprints, which may be used to identify patient-specific arrays of TAA. This may enable a multi-epitope based immunotherapy with improved prospects of clinical tumor rejection.
Mathiassen
S
S
Institute of Medical Anatomy, University of Copenhagen, Copenhagen, Denmark.
Lauemøller
S L
SL
Ruhwald
M
M
Claesson
M H
MH
Buus
S
S
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics; D006183:H-2 Antigens / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015996:Survival Rate; D013945:Thymoma / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D014407:Tumor Cells, Cultured; D014611:Vaccination
D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D005656:Fungal Proteins; D006183:H-2 Antigens; D010455:Peptides; C086930:RAD50 protein, S cerevisiae; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins