title: Epitope clustering in regions undergoing efficient proteasomal processing defines immunodominant CTL regions of a tumor antigen.
abstract: Identification of immunodominant CD8(+) T cell responses to frequently expressed tumor antigens across MHC class I polymorphism is essential for the implementation of cancer immunotherapy. However, the key factors that determine immunodominance are not fully understood. Because of its frequent expression in tumors and its spontaneous immunogenicity, NY-ESO-1 is a prime target of cancer vaccines and an ideal model antigen for elucidating the molecular basis of immunodominant tumor-specific CD8(+) T cell responses. Here, we have assessed CD8(+)T cell responses to full-length NY-ESO-1 in cancer patients. We identified 3 immunodominant regions of the protein located within 3 distinct clusters of MHC class I binding sequences that co-localize with previously defined clusters of MHC class II binding sequences, are predicted to be hydrophobic and undergo efficient proteasomal processing. Our results support the concept that epitope clustering within defined protein regions identifies tumor antigen immunodominant regions and suggest a general strategy for their identification.
authors.affiliation: Ludwig Institute Clinical Trial Center, Department of Medicine, Columbia University College of Physicians and Surgeons, 650 West 168th Street, Black Building Room 20-09, New York, NY 10032, USA. dv2117@columbia.edu <dv2117@columbia.edu>
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lévy
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Godefroy
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Naira E
authors.initials: NE
authors.lastname: Souleimanian
authors.forename: Julia
authors.initials: J
authors.lastname: Karbach
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.forename: Charles S
authors.initials: CS
authors.lastname: Hesdorffer
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Elke
authors.initials: E
authors.lastname: Jager
authors.forename: Maha
authors.initials: M
authors.lastname: Ayyoub
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D046988:Proteasome Endopeptidase Complex