The goal of this project is to develop effective strategies for the induction of a cytotoxic T cell response against the Thomsen-Fredienreich antigen, a well defined carbohydrate antigen expressed in carcinomas of various origin but not in normal tissues. The investigator's approach involves the induction of three different TF-specific T cell subsets: 1) CD8+ TCR alpha/beta T cells; 2) TCR gamma/delta T cells; 3) CD4- CD8- and/or CD8+ CD1-restricted T cells. CD8+ MHC class I restricted T cells are clearly relevant in tumor rejection, as previously extensively demonstrated. However, gamma /delta T cells and CD1-restricted T cells are also potentially important in tumor immunology. In particular, both gamma/delta and CD1-restricted alpha/beta T cells have recently been shown to be able to recognize carbohydrate ligands. This, together with the lack of MHC restriction, make those T cell subsets of particular interest from the point of view of vaccine development. Overall, in this application, the investigator will attempt to define vaccination strategies that can be used in the treatment of a broad range of neoplastic diseases. To induce TF-specific T cells in vivo, he will generate glycopeptides where the peptide backbones are either natural sequences or have amino acid sides with small side chains (A, G, or S?) containing the appropriate MHC anchor residues. For gamma /delta and CD1 restricted T cell induction, the immunogenic capacity of glycolipids, as well as glycopeptides delivered by professional antigen presenting cells, will also be investigated. The relevance of TF-specific CD8+, gamma/delta, or CD1-restricted T cells in tumor rejection will be analyzed using the murine mammary adenocarcinoma induced by TA3-Ha cells as an experimental model. Two strategies will be compared: 1) passive immunotherapy by T cell transfer with selected T cell clones; and 2) active vaccination with the glycopeptides and glycolipids to generate a TF-specific T cell response.
| Diaz-de-Durana, Yaiza; Mantchev, George T; Bram, Richard J et al. (2006) TACI-BLyS signaling via B-cell-dendritic cell cooperation is required for naive CD8+ T-cell priming in vivo. Blood 107:594-601 |
| Xu, Yanfei; Sette, Alessandro; Sidney, John et al. (2005) Tumor-associated carbohydrate antigens: a possible avenue for cancer prevention. Immunol Cell Biol 83:440-8 |
| Xu, Yanfei; Gendler, Sandra J; Franco, Alessandra (2004) Designer glycopeptides for cytotoxic T cell-based elimination of carcinomas. J Exp Med 199:707-16 |
| Franco, A; Yokoyama, T; Huynh, D et al. (1999) Fine specificity and MHC restriction of trinitrophenyl-specific CTL. J Immunol 162:3388-94 |
