Investigation into the role of macrophages heterogeneity on solid tumour aggregations

Abstract

Macrophages are one of the most important immune cell populations that can be found inside solid tumours. For a long time, it was thought that these cells have an anti-tumour role, but relatively recent research has shown that they can have both anti-tumour and pro-tumour roles as determined by their phenotypes. Due to the heterogeneity and plasticity of macrophage population, with cells changing their phenotypes in response to the tumour microenvironment, it is difficult to fully understand their role inside the solid tumours. Here we consider a mathematical modelling and computational approach to investigate the change in macrophages phenotypes (either determined by the tumour itself, or by external interventions) on overall tumour growth/control/decay. To this end we consider two simple models: one focusing on two extreme phenotypes (the M1 anti-tumour cells, and the M2 pro-tumour cells), and one considering a macrophage population structured by a continuous phenotype variable. We investigate their asymptotic dynamics (through steady-state analysis), as well as their transient behaviours (through numerical simulations). We show that while a re-polarisation of the phenotype of macrophages, as considered by many recent experimental studies, can lead to tumour control, for tumour elimination it is required that macrophages are fully functional (i.e., the rate at which they kill tumour cells is high). We also show that a mixed macrophage’s phenotype can keep the tumour under control in a state of dormancy. Moreover, an increase in this mixed phenotype can cause a delay in tumour reduction (accompanied by a larger tumour reduction), as well as a delay in tumour relapse.