Development of tumor-associated antigen (TAA)-specific T cell responses in heavily-tolerized mice requires vaccination with peptide variants that target T cells with decreased responsiveness to TAA (131.7)

Abstract

Abstract Vaccination with peptide variants of a tumor-associated antigen (TAA) can induce T cell responses that cross-react with the TAA. Using the gp70(423-431, AH1) epitope of endogenous MuLV as our model TAA, we have developed peptide variants that, unlike AH1 itself, induce AH1-reactive T cell responses upon vaccination of BALB/c mice. Two of these variants, A5 and 39, induce robust AH1-reactive responses in young mice. These variants were used to vaccinate aging mice, which have increased expression of and tolerance to gp70 protein. Variant-39 consistently induced AH1-specific responses, regardless of levels of gp70 expression in individual mice. Conversely, variant-A5 did not induce AH1-specific responses in most aging mice tested. The inability of variant-A5 to induce AH1-specific responses in individual mice correlated with increased gp70 expression. We hypothesized that variant-39 expands AH1-specific cells that are less reactive to AH1 than those expanded by variant-A5, thus impeding tolerance by peripheral AH1 presentation. Analyzing variant-induced responses in young mice, we determined that T cells expanded by variant-39 indeed have diminished function upon stimulation with AH1 relative to those elicited by variant-A5. These findings suggest that tumor vaccines require TAA variants that target cross-reactive T cell repertoires with low enough reactivity to TAA to avoid tolerance in the periphery, yet sufficient reactivity to provide effective antitumor responses.