Design of a MUC1-based cancer vaccine

Abstract

The epithelial type 1 transmembrane mucin MUC1 is long-established as a marker for monitoring recurrence of breast cancer, and beyond its diagnostic marker qualities, it is a promising target for immunotherapeutic strategies to treat cancer by active specific immunization. The mucin is able to break tolerance and to induce humoral immune responses in healthy subjects and in cancer patients, but the response is generally weak. These natural responses to tumour-associated MUC1 glycoforms indicate that antibody reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes. To overcome the weak immunogenicity of heavily O-glycosylated MUC1, the question of whether O-linked glycans remain intact during processing in the MHC class II pathway was addressed. Attempts were made to define site-specific O-glycosylation and the structural requirements for efficient endosomal proteolysis by cathepsin L in dendritic cells. A fraction of glycopeptides survive the processing machinery, and have the capacity to bind to MHC class II and to activate sub-populations of glycopeptide-specific helper T-cell clones as a prerequisite for strong and long-lasting immune responses to MUC1-positive tumours. Moreover, studies on clusters of sequence-variant repeats, which are interspersed in the repeat domain of MUC1 at high frequency, have revealed that a limited set of concerted amino-acid replacements (Asp-Thr0-Arg1-Pro10 to Glu-Ser0-Arg1-Ala10) contributes considerably to increased peptide flexibility and to under-glycosylation of sequence-variant repeats which in concert modify immunological features of the mucin. Peptides and glycopeptides with the immunodominant DTR (Asp-Thr-Arg) or with the variant ESR (Glu-Ser-Arg) motif, and highly immunogenic peptides of the degenerate repeats that flank the repeat domain are currently evaluated as potential targets in multi-epitopic adjuvant-based vaccine strategies for their capacity to induce cytotoxic T-cell responses.