title: HLA anchor optimization of the melan-A-HLA-A2 epitope within a long peptide is required for efficient cross-priming of human tumor-reactive T cells.
abstract: The uptake and long-term cross-presentation of tumor Ag long peptides (LP) by dendritic cells (DC) make them attractive cancer vaccine candidates. However, it remains to be established whether LP can prime long-lived tumor-reactive CTL and whether other cell types are able to cross-present them. Using HLA-A2 healthy donor and melanoma patient-derived PBMC, we studied the in vitro cross-priming potential of Melan-A 16-40 LP bearing the HLA-A2-restricted epitope 26-35 or its analog 26-35(A27L) and compared it to the priming capacity of the short analog. We then addressed LP priming capacity in vivo using HLA-A2 mice. We also studied LP cross-presentation by monocyte-derived DC, plasmacytoid DC, monocytes, and B cells. We showed that the modified LP gave rise to high and sustained cross-presentation by monocyte-derived DC. This led to cross priming in vitro and in vivo and to expansion of long-lived tumor-reactive cytotoxic T cells. In contrast, the LP containing the natural 26-35 epitope primed specific T cells poorly, despite its long-lived cross-presentation, and T cells primed against the short analog were short-lived. We further showed that LP cross-presentation is restricted to monocytes and conventional DC. These results document for the first time, to our knowledge, the strong immunogenicity of a human tumor Ag LP. Of note, they underscore that this property is critically dependent on sufficient HLA binding affinity and/or TCR ligand potency of the cross-presented epitope. We conclude that LP fulfilling this requirement should be used as tumor vaccines, together with DC maturating agents, especially the Melan-A 16-40(A27L) LP, for the treatment of HLA-A2(+) melanoma patients.
authors.affiliation: INSERM, Unité Mixte de Recherche 892, F-44007 Nantes, France.
authors.forename: Joë-Marc
authors.initials: JM
authors.lastname: Chauvin
authors.forename: Pierre
authors.initials: P
authors.lastname: Larrieu
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabayrouse
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
authors.forename: Renée
authors.initials: R
authors.lastname: Lengagne
authors.forename: Juliette
authors.initials: J
authors.lastname: Desfrançois
authors.forename: Nathalie
authors.initials: N
authors.lastname: Labarrière
authors.forename: Francine
authors.initials: F
authors.lastname: Jotereau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism* / Q000502:physiology; D015789:HLA-A2 Antigen / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D058965:MART-1 Antigen / Q000378:metabolism* / Q000502:physiology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D010446:Peptide Fragments