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 characterized. To elucidate these mechanisms, we developed a human-parametrized, 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 (MHC-I) receptors of dendritic cells (DCs) 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 DCs and T cells that interact subsequent to DC migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.
J R Soc Interface
T-cell dynamics, antigen presentation, cancer vaccine, cytotoxic T-Lymphocyte activation, lymph node, modelling and simulation, Animals, Antigen Presentation, Antigens, Neoplasm, Cancer Vaccines, Computer Simulation, Dendritic Cells, Histocompatibility Antigens Class I, Humans, Lymph Nodes, Models, Immunological, Peptides, T-Lymphocytes, Cytotoxic