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

Authored by Liam V Brown, Eamonn A Gaffney, Jonathan Wagg, Mark C Coles

Date Published: 2018

DOI: 10.1098/rsif.2018.0041

Sponsors: United Kingdom Engineering and Physical Sciences Research Council (EPSRC)

Platforms: C++

Model Documentation: Other Narrative

Model Code URLs: https://ora.ox.ac.uk/objects/uuid:c4fbb0ed-3ab5-4d10-b051-d0bd14da9890

Abstract

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.

Tags

behavior Dynamics Lymph node Global sensitivity-analysis Mhc class-i Antigen presentation Number Vivo Cancer vaccine Modelling and simulation T-cell dynamics Cytotoxic t-lymphocyte activation Dendritic cell-migration 2-photon microscopy Molecule