An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination

Tumour immunotherapy is dependent upon activation and expansion of tumour targetting immune cells, known as Cytotoxic T-Lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterised. To elucidate these mechanisms, we developed a human parameterised, in silico, agent based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour specific immune-response inducing peptides (cognate antigen) from the major histocompatibility class I receptors (MHC-I) of dendritic cells originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of dendritic cells and T cells that interact subsequent to dendritic cell migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.