title: CTL activation using the natural low-affinity epitope 222-229 from tyrosinase-related protein 1 leads to tumor rejection.
abstract: Vaccine strategies for cancer immunotherapy have focused on peptide ligands with high affinity for MHC class I. Largely, these vaccines have not been therapeutic. We have examined the peptide specificity of a strongly protective T-cell response that eradicates established B16 melanoma and find that the recognized epitope is generated by a low-affinity MHC class I ligand from tyrosinase-related protein 1 (TRP1). Cytotoxic T-cell responses are induced against TRP1(222-229) by several vaccination schemes using a Toll-like receptor agonist, T regulatory cell depletion, or the immune modulator B7-DCXAb to drive immunity. TRP1(222) CTL are generated from multiple antigen sources, including antigens expressed by tumors growing in situ, tumor cell lysates, and peptide vaccines. The key finding in this study is that protection from freshly implanted or established B16 tumors is primarily mediated by TRP1(222)-specific CTL and not by CTL specific for more traditional melanoma antigens such as TRP2 or gp100. This finding challenges the assumption that the optimal peptide antigens for cancer vaccines are high-affinity MHC ligands. We propose that when administered appropriately, native low-affinity MHC ligands are optimal inducers of immunotherapeutic CTL.
authors.affiliation: Department of Immunology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Pavelko
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hansen
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007371:Interferon-gamma; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse