Investigating Macrophages Plasticity Following Tumour–Immune Interactions During Oncolytic Therapies

Abstract

Over the last few years, oncolytic virus therapy has been recognised as a promising approach in cancer treatment, due to the potential of these viruses to induce systemic anti-tumour immunity and selectively killing tumour cells. However, the effectiveness of these viruses depends significantly on their interactions with the host immune responses, both innate (e.g., macrophages, which accumulate in high numbers inside solid tumours) and adaptive (e.g., T cells). In this article, we consider a mathematical approach to investigate the possible outcomes of the complex interactions between two extreme types of macrophages (M1 and M2 cells), effector T cells and an oncolytic Vesicular Stomatitis Virus (VSV), on the growth/elimination of B16F10 melanoma. We discuss, in terms of VSV, and macrophages levels, two different types of immune responses which could ensure tumour control and eventual elimination. We show that both innate and adaptive anti-tumour immune responses, as well as the oncolytic virus, could be very important in delaying tumour relapse and eventually eliminating the tumour. Overall this study supports the use mathematical modelling to increase our understanding of the complex immune interaction following oncolytic virotherapies. However, the complexity of the model combined with a lack of sufficient data for model parametrisation has an impact on the possibility of making quantitative predictions.

Oscillations in a Spatial Oncolytic Virus Model

“…This conclusion is further confirmed by models that include immune response. Storey et al (76) talk about an intermediate immune response for optimal treatment outcome, and Eftimie et al (19) show the existence of multi-stability and even multi-instability, which is a strong indication of irregular and chaotic behavior.…”

“…We note that the majority of mathematical modeling has focused on temporal dynamics of tumor-virus or tumor-virus-immune interaction because of the availability of temporal data. Some of these models are based on ordinary differential equations (40; 5; 20; 19; 67; 61; 79; 39; 76), while other models are based on delay differential equations (13; 15; 86; 51; 87).…”

The Multifaceted Role of Macrophages in Oncolytic Virotherapy

“…Over time, sufficient inflammation must be permitted and, when the restriction on the innate immune system has been removed, an anti-tumour response can be developed. Viral pharmacokinetics, pharmacodynamics, and kinetics of innate immune suppression in relation to the number of initial viral replication cycles require further investigation, ultimately supported by mathematical modelling of interactions and making quantitative and substantiated predictions [ 163 ]. Moreover, it needs to be elucidated whether this approach would compromise the safety profile.…”

A mathematical model for the role of macrophages in the persistence and elimination of oncolytic viruses

“…Description of the interactions between the M1/M2 macrophages and an oncolytic VSV, as given by equations (2.1a)-(2.1d). The model was inspired by the experimental studies in [50,38,48] (where the VSV infects only the M2 cells but not the M2 cells), and the mathematical modelling studies in [13,14] (which focused only on the anti-viral effect of M1 cells, and did not consider the infection of macrophages). Even if we focus on an ocolytic virus, here we do not investigate the effect of the tumour on these VSV-macrophages interactions; this aspect will be investigated in a further study [2].…”

“…Mathematical and computational approaches have been used over the past years to investigate the interactions between viruses and macrophages in the context of cancer [9,13,14,35,37], or in the context of different viral infections [5,17,18,21,25,28,34,41,61]. While the latest models that focus on oncolytic viruses differentiate between the anti-tumour and anti-viral roles of M1 and M2 macrophages, the models that focus on viral infections do not usually differentiate between the roles of M1 and M2 cells in eliminating/spreading the infection.…”