Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of interactions with the center of the peptide

Class I major histocompatibility complex (MHC) molecules bind short peptide s derived from proteins synthesized within the cell. These complexes of pep tide and class I MHC (pMHC) are transported from the endoplasmic reticulum to the cell surface. If a clonotypic T cell receptor expressed on a circula ting T cell binds to the pMHC complex, the cell presenting the pMHC is kill ed. In this manner, some tumor cells expressing aberrant proteins are recog nized and removed by the immune system. However, not all tumors are recogni zed efficiently. One reason hypothesized for poor T cell recognition of tum or-associated peptides is poor binding of those peptides to class I MHC mol ecules. Many peptides, derived from the proto-oncogene HER-2/neu have been shown to be recognized by cytotoxic T cells derived from HLA-A2(+) patients with breast cancer and other adenocarcinomas. Seven of these peptides were found to bind with intermediate to poor affinity. In particular, GP2 (HER- 2/neu residues 654-662) binds very poorly even though it is predicted to bi nd web based upon the presence of the correct HLA-A2.1 peptide-binding moti f. Altering the anchor residues to those most favored by HLA-A2.1 did not s ignificantly improve binding affinity. The crystallographic structure shows that unlike other class I-peptide structures, the center of the peptide do es not assume one specific conformation and does not make stabilizing conta cts with the peptide-binding cleft.