Tolerance and Immunity to Tumor‐associated Antigen MUC1 in MUC1.Tg Mice

Numerous adenocarcinomas aberrantly express a hypoglycosylated form of human mucin 1 (MUC1), containing epitopes with tumor‐associated mono‐ and disaccharide moieties including Tn, sialyl‐Tn, and TF antigens along with bare protein backbone. In the MUC1 transgenic mouse the immune system maintains a level of tolerance to MUC1 peptides, most notably in decreased CD4 T cell help. We are further examining the mechanisms of tolerance to MUC1 peptide (self), as compared to responses to a tumor‐associated MUC1 glycopeptide (non‐self), which should not be subject to tolerance. We have cloned a MUC1 glycopeptide‐specific MHC‐Class II restricted TCR (RFT). that is currently being used to generate TCR transgenic mice for comparative in vivo studies with MUC1 peptide‐specific TCR transgenic mice previously generated. Preliminary adoptive transfer studies have indicated that peptide‐specific TCR transgenic T cells are able to persist in both wild type and MUC1.Tg mice, but upon MUC1 immunization, only the cells in wild type recipients appear activated. Taken together our studies explore the differences in immune responsiveness to two different tumor‐associated forms of MUC1 in a preclinical model where MUC1 is endogenously expressed and functioning and will enable us to tailor more effective and safe MUC1 vaccination strategies. (supported by NIH grants T32CA82084 and RO1CA56103; J.G. by grants from CBCRA/CCS)