| One approach to enhance the T cell response to tumors is vaccination with mimotopes, mimics of tumor epitopes. While mimotopes can stimulate proliferation of T cells that recognize tumor-associated antigens (TAA), this expansion does not always correlate with control of tumor growth. I hypothesized that vaccination with mimotopes of optimal affinity in this interaction will improve antitumor immunity. Using a combinatorial peptide library and a TAA-specific T cell clone I identified a panel of mimotopes that, when complexed with MHC, bind the TAA-specific TCR with a range of affinities. As expected, in vitro assays showed that the affinity of the TCR-peptide-MHC interaction correlates with activity of the T cell clone. However, only vaccination with mimotopes in the range of intermediate affinities elicits functional T cells and provides protection against tumor growth in vivo. Vaccination with mimotopes with the highest affinity TCR-peptide-MHC interactions elicits TAA-specific T cells to the tumor, but does not control tumor growth at any of the peptide concentrations tested. Further analyses of these T cells showed functional defects in IFNgamma production by both splenocytes and tumor infiltrating lymphocytes (TIL). T cell function was lost during the late stages of tumor growth suggesting that the T cell dysfunction requires the presence of tumor. Together, these studies suggest that stimulation of an antitumor response by mimotope vaccines may be optimal with peptides that increase but do not maximize the affinity of the TCR-peptide-MHC interaction. |
