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cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2Db in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2Db/Trh4. Comparison of the crystal structures of the H-2Db/Trh4-p3P and H-2Db/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur-\u03c0 interactions with H-2Db residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability.","bibjson":{"author":[{"initials":"I","lastname":"Hafstrand","name":"Hafstrand I"},{"initials":"EM","lastname":"Doorduijn","name":"Doorduijn EM"},{"initials":"R","lastname":"Sun","name":"Sun R"},{"initials":"A","lastname":"Talyzina","name":"Talyzina A"},{"initials":"M","lastname":"Sluijter","name":"Sluijter M"},{"initials":"S","lastname":"Pellegrino","name":"Pellegrino S"},{"initials":"T","lastname":"Sandalova","name":"Sandalova T"},{"initials":"AD","lastname":"Duru","name":"Duru AD"},{"initials":"T","lastname":"van Hall","name":"van Hall T"},{"initials":"A","lastname":"Achour","name":"Achour A"}],"identifier":[{"id":"10.4049/jimmunol.1700228","type":"doi"},{"id":"29507106","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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