Heukamp, Lukas Carl; (2000) Cellular immune responses against the tumour associated polymorphic epithelial mucin MUC1. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The human epithelial mucin MUC1 is expressed on the apical surface of a large number of normal epithelial tissues, including the ducts of the breast, ovary, pancreas, lung and colon. Adenocarcinomata that arise from these tissues can show marked over expression of MUC1, as well as aberrant glycosylation and loss of apical distribution of this mucin. These observations led to the attempt to use MUC1 a potential target for tumour immunotherapy. The work described in this thesis aims to evaluate cellular immune responses directed against the MUC1 antigen, using mouse model systems. The project addresses fundamental questions relating to the feasibility of using MUC1-based antigens for tumour immunotherapy, and has led to the identification of MHC class I-restricted epitopes both in mice and in humans; that may have clinical relevance. Firstly, the induction of MUC1-specific CTL lines and their characterisation in a C57BL/6 mouse model is described. This includes mapping of the dominant CTL epitope recognised by MUC1-specific CTL and analysis of anti-tumour effects of these CTL in vivo. Adoptive transfer of CTL cultured in vitro into MUC1 transgenic mice, where human MUC1 is expressed as a self antigen, has allowed evaluation of immunogenicity and tumour protection in a setting in which autoimmunity may occur. The results demonstrate that the host can tolerate effective anti-tumour immune responses to MUC1 without induction of autoimmunity. The second major part of the work aimed to identify human MHC class I-restricted MUC1-derived epitopes. The merits of the different possible approaches for epitope identification are discussed and the identification of HLA A*0201-restricted epitopes is described. Potential MHC binding peptides were identified by motif scoring. These peptides were then analysed for binding and complex stability with HLA-A*0201. The immunogenicity and physiological relevance of these peptides is shown by induction of CTL responses and tumour protection in a transgenic mouse model expressing HLA A*0201-Kb.

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