Abstract
The success of oncolytic virotherapies depends on the tumour microenvironment, which contains a large number of infiltrating immune cells. In this theoretical study, we derive an ODE model to investigate the interactions between breast cancer tumour cells, an oncolytic virus (Vesicular Stomatitis Virus), and tumour-infiltrating macrophages with different phenotypes which can impact the dynamics of oncolytic viruses. The complexity of the model requires a combined analytical-numerical approach to understand the transient and asymptotic dynamics of this model. We use this model to propose new biological hypotheses regarding the impact on tumour elimination/relapse/persistence of: (i) different macrophage polarisation/re-polarisation rates; (ii) different infection rates of macrophages and tumour cells with the oncolytic virus; (iii) different viral burst sizes for macrophages and tumour cells. We show that increasing the rate at which the oncolytic virus infects the tumour cells can delay tumour relapse and even eliminate tumour. Increasing the rate at which the oncolytic virus particles infect the macrophages can trigger transitions between steady-state dynamics and oscillatory dynamics, but it does not lead to tumour elimination unless the tumour infection rate is also very large. Moreover, we confirm numerically that a large tumour-induced M1$\to$M2 polarisation leads to fast tumour growth and fast relapse (if the tumour was reduced before by a strong anti-tumour immune and viral response). The increase in viral-induced M2$\to$M1 re-polarisation reduces temporarily the tumour size, but does not lead to tumour elimination. Finally, we show numerically that the tumour size is more sensitive to the production of viruses by the infected macrophages.
Highlights
Oncolytic viral therapies have become one of the most promising therapies for cancer, due to the ability of some viruses to replicate inside tumour cells without damaging normal tissue cells [50]
We derive an ODE model to investigate the interactions between breast cancer tumour cells, an oncolytic virus (Vesicular Stomatitis Virus), and tumour-infiltrating macrophages with different phenotypes which can impact the dynamics of oncolytic viruses
For b/c > 1 this asymptotic tumour size increases at a much slower rate. These results suggest that the non-linearity in model dynamics plays a role in tumour evolution when the same number of virus particles are released by the infected tumour cells and infected macrophages
Summary
Oncolytic viral therapies have become one of the most promising therapies for cancer, due to the ability of some viruses (i.e., oncolytic viruses) to replicate inside tumour cells without damaging normal tissue cells [50] In addition to their ability to selectively replicate inside cancer cells, which leads to the destruction of these cells, oncolytic viruses can trigger anti-tumour immune responses [34]. These anti-tumour immune responses are counterbalanced by anti-viral immune responses which eliminate the virus particles from the body [14]. The different roles of macrophages on virus elimination and/or persistence might be explained by the heterogeneity of macrophage population These immune cells can have a variety of polarisation phenotypes, depending on the microenvironment they are in, and on the activation stimuli. Recent studies have shown that a promising oncolytic virus, the Vesicular Stomatitis Virus (VSV), can infect and replicate inside M2 cells but not inside M1 cells [60]
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