Immunology of MUC1 and Advancements in the Development of MUC1 Glycopeptide Tumor Vaccines: An Update
Pp. 615-636 (22)
Evidence has accumulated that carbohydrate-peptide epitopes do play a role in
classical MHC-mediated immune responses. T-cell recognition of O-glycosylated peptides
is potentially of high biomedical significance, because it can mediate the immune protection
against microorganisms, and in particular the vaccination in anti-tumor therapies.
The epithelial type 1 transmembrane mucin MUC1 is established as a marker for
monitoring recurrence of breast cancer and is a promising target for immunotherapeutic
strategies to treat cancer by active specific immunization. Natural human immune
responses to the tumor-associated glycoforms of the mucin indicate that antibody
reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes.
To overcome the weak immunogenicity of the tumor-associated glycoform of MUC1 in
experimental immunization, attempts were made to get insight into the molecular
requirements for effective antigen processing and to identify class I and II processing
permissive glycosylation sites. Evidence based on work with CD4+ T-hybridomas
confirms that O-glycopeptide products of the immunoproteasomal or endosomal
processing machineries can be effectively presented to T-cells and that glycans can
form integral parts of the TCR defined epitopes. Immunization strategies in human
MUC1 transgenic mice have demonstrated that different from nonglycosylated epitopes
the glycoforms are recognized as foreign by the immune system and can effectively
break immunotolerance. Based on these findings superior vaccines have been designed
and successfully applied in transgenic mice that have a multi-epitope composition in
common by comprising self-adjuvanting, APC-targeting and antigen-specific epitopes.
MUC1, mucin, immunology, tumor vaccine, cancer, glycopeptide, Oglycosylation,
antigenicity, immunogenicity, immunological processing, MHC
presentation, MHC class I, MHC class II, proteasome.
Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, Germany.