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Cellular mucins: targets for immunotherapy
V Apostolopoulos1, I F McKenzie
1Austin Research Institute, Heidelberg, Victoria, Australia.
Abstract:
Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucin 1 (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide--shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.
Insights
Mucin 1 (MUC1) cancer vaccines target unique MUC1 epitopes on cancer cells. These epitopes, including the APDTR peptide, stimulate immune responses for potential cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Mucins, particularly Mucin 1 (MUC1), are overexpressed and aberrantly glycosylated in various adenocarcinomas, presenting unique epitopes absent in normal tissues.
- These MUC1 alterations include a 10-fold increase in expression, ubiquitous presence, and the appearance of novel carbohydrate and peptide neo-epitopes.
Purpose of the Study:
- To explore the potential of MUC1 as a target for cancer immunotherapy, specifically in the development of vaccines for MUC1-expressing cancers.
- To investigate the immunogenicity of MUC1 epitopes and their role in stimulating anti-cancer immune responses.
Main Methods:
- Cloning of mucin cDNAs, particularly MUC1, to identify immunogenic regions.
- Characterization of peptide epitopes, such as APDTR, within the MUC1 variable number of tandem repeats (VNTR).
- In vitro stimulation of cytotoxic T lymphocytes (CTLs) from cancer patients' lymph nodes against MUC1 peptides.
Main Results:
- Identification of a highly immunogenic peptide within the MUC1 VNTR, capable of eliciting strong antibody production in mice.
- Demonstration that human breast cancer patients possess CTL precursors reactive to MUC1 peptides, notably APDTR.
- Observation that these tumor-associated CTLs are non-MHC restricted.
Conclusions:
- MUC1-derived peptides and neo-carbohydrate epitopes are viable targets for cancer immunotherapy.
- Development of MUC1-based cancer vaccines using synthetic carbohydrates or peptides conjugated with adjuvants is underway.
- Clinical trials are ongoing to assess the immunogenicity and efficacy of these novel cancer vaccines.