title: HLA-independent heterogeneity of CD8+ T cell responses to MAGE-3, Melan-A/MART-1, gp100, tyrosinase, MC1R, and TRP-2 in vaccine-treated melanoma patients.
abstract: An important element in melanoma vaccine construction is to identify peptides from melanoma-associated Ags that have immunogenic potential in humans and are recognized by CD8+ T cells in vivo. To identify such peptides, we evaluated HLA-A*02+ melanoma patients immunized to a polyvalent vaccine containing multiple Ags, including MAGE-3, Melan-A/MART-1, gp100, tyrosinase, melanocortin receptor (MC1R), and dopachrome tautomerase (TRP-2). Using a filter spot assay, we measured peripheral blood CD8+ T cell responses, before and after immunization, to a panel of 45 HLA-A*0201-restricted peptides derived from these Ags. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*0201. Vaccine treatment induced peptide-specific CD8+ T cell responses to 22 (47.8%) of the peptides. The most striking finding was the HLA-independent heterogeneity of responses to both peptides and Ags. All responding patients reacted to different combination of peptides and Ags even though the responding patients were all A*0201+ and the peptides were all A*0201-restricted. From 9 to 27% of patients developed a CD8+ T cell response to at least one peptide from each Ag, but no more than 3 (14%) reacted to the same peptide from the same Ag. This heterogeneity of responses to individual peptides and Ags in patients with the same haplotype points to the need to construct vaccines of multiple peptides or Ags to maximize the proportion of responding patients.
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University Medical Center, NY 10016, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Reynolds
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: R
authors.initials: R
authors.lastname: Oratz
authors.forename: R L
authors.initials: RL
authors.lastname: Shapiro
authors.forename: D
authors.initials: D
authors.lastname: Johnston
authors.forename: M
authors.initials: M
authors.lastname: Fotino
authors.forename: J C
authors.initials: JC
authors.lastname: Bystryn
mesh_terms: D000483:Alleles; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018572:Disease-Free Survival; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007114:Immunization; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D014442:Monophenol Monooxygenase / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D018043:Receptors, Corticotropin / Q000276:immunology; D044101:Receptors, Melanocortin; D016896:Treatment Outcome; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase