The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability
| Autor: | Adnane Achour, Renhua Sun, T. van Hall, Tatyana Sandalova, Marjolein Sluijter, Elien M. Doorduijn, A. Talyzina, I. Hafstrand, Sara Pellegrino, Adil Doganay Duru |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antigenicity Proline T cell Immunology Epitopes T-Lymphocyte Mice Transgenic Peptide Major histocompatibility complex Cancer Vaccines Epitope Mice 03 medical and health sciences Immune system Antigens Neoplasm MHC class I medicine Animals Immunology and Allergy Histocompatibility Antigen H-2D chemistry.chemical_classification biology Protein Stability Chemistry Immunogenicity Membrane Proteins Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure biology.protein Peptides |
| Zdroj: | The Journal of Immunology. 200:2860-2868 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1700228 |
| Popis: | Human 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–π 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|