Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201 Implications for WT1-based cancer therapeutics

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 1 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 (C) 2010 Elsevier Ltd All rights reserved