Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A0201: Implications for WT1-based cancer therapeutics

• Published in: Molecular immunology Vol. 47; no. 15; pp. 2519 - 2524
• Main Authors: Borbulevych, Oleg Y., Do, Priscilla, Baker, Brian M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2010
• Subjects: AFFINITY; Antigen Presentation; BASIC BIOLOGICAL SCIENCES; Cancer Vaccines; CHAINS; Crystallography, X-Ray; ELECTROSTATICS; ENGINEERS; Epitopes - chemistry; Epitopes - immunology; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; HISTOCOMPATIBILITY COMPLEX; HLA-A Antigens - chemistry; HLA-A Antigens - immunology; HLA-A2 Antigen; Humans; Models, Molecular; NEOPLASMS; Neoplasms - genetics; Neoplasms - therapy; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - therapeutic use; Peptide/MHC; PEPTIDES; Point Mutation; Polymorphism, Single Nucleotide; Protein Conformation; Protein Engineering; Protein Stability; STABILITY; Static Electricity; Structure; Structure-Activity Relationship; SURFACE POTENTIAL; TRANSCRIPTION FACTORS; VACCINES; WT1; WT1 Proteins - chemistry; WT1 Proteins - genetics; WT1 Proteins - therapeutic use; Cancer vaccines; Peptide/MHC; Structure; WT1; Electrostatics
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2010.06.005

Presentation of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126–134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex.