Tumour vaccines aim to elicit potent immunity against a tumour, but one obstacle that they must overcome is the poor reactivity of T cells for tumour-associated antigens (TAAs). Mimotopes are mimics of tumour epitopes that can be used in vaccines to increase the number and function of TAA-specific T cells, but tumour regression in patients often does not correlate with the magnitude of the T-cell responses that are caused. Jill Slansky and colleagues have now shown that it is not the peptides that bind with highest affinity to the T-cell receptors (TCRs) that stimulate the most effective anti-tumour response, but those that bind with moderate affinity.

The authors identified six mimotopes from a combinatorial peptide library that, when complexed with the major histocompatibility complex molecule H-2Ld, increased affinities for a representative TCR that recognizes the AH1 T-cell epitope from a mouse colon tumour. All six mimotopes stimulated the production of interferon-γ (IFNγ), which is a potent activator of macrophages and is crucial for an effective response against solid tumours, from a T-cell clone in cell culture. They also all showed a correlation between their binding affinity to the TCR and their functional stimulation of the T cells.

So, does this correlation between binding affinity and functional stimulation hold in vivo? Mice were first vaccinated with mimotopes and then challenged with colon tumour cells. The AH1 peptide provided no protection from tumour growth, as expected. Unexpectedly, however, the intermediate-affinity mimotopes were most effective — a significant number of mice remained tumour free for more than 60 days compared with mice vaccinated with high-affinity mimotopes. When the high-affinity peptides were examined further, Slansky and colleagues found that although numbers of AH1-specific T cells with the expected expression of activation markers were increased in the mice, these T cells had defects in effector function. Tumour-infiltrating T cells in the mice that were vaccinated with high-affinity mimotopes produced significantly less IFNγ than those in mice that were vaccinated with the intermediate-affinity mimotopes. Interestingly, this was specific to stimulation with the AH1 mimotopes, as treatment of the mice with other T-cell stimuli induced higher IFNγ production.

These data show that it is the quality and not the quantity of the T-cell response that determines the effectiveness of the immune response to these tumour vaccines in vivo. This should be taken into account when designing peptide vaccines for anticancer therapy in the future.