Mathematical Modeling and Analysis of CD200-CD200R in Cancer Treatment.

CD200 is a cell membrane protein that binds to its receptor, CD200 receptor (CD200R). The CD200 positive tumor cells inhibit the cellular functions of M1 and M2 macrophages and dendritic cells (DCs) through the CD200-CD200R complex, resulting in downregulation of Interleukin-10 and Interleukin-12 productions and affecting the activation of cytotoxic T lymphocytes. In this work, we provide two ordinary differential equation models, one complete model and one simplified model, to investigate how the binding affinities of CD200R and the populations of M1 and M2 macrophages affect the functions of the CD200-CD200R complex in tumor growth. Our simulations demonstrate that (i) the impact of the CD200-CD200R complex on tumor promotion or inhibition highly depends on the binding affinity of the CD200R on M2 macrophages and DCs to the CD200 on tumor cells, and (ii) a stronger binding affinity of the CD200R on M1 macrophages or DCs to the CD200 on tumor cells induces a higher tumor cell density in the CD200 positive tumor. Thus, the CD200 blockade would be an efficient treatment method in this case. Moreover, the simplified model shows that the binding affinity of CD200R on macrophages is the major factor to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are significantly different to each other. On the other hand, both the binding affinity of CD200R and the population of macrophages are the major factors to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are close to each other. We also analyze the simplified model to investigate the dynamics of the positive and trivial equilibria of the CD200 positive tumor case and the CD200 deficient tumor case. The bifurcation diagrams show that when M1 macrophages dominate the population, the tumor cell density of the CD200 positive tumor is higher than the one of CD200 deficient tumor. Moreover, the dynamics of tumor cell density change from tumor elimination to tumor persistence to oscillation, as the maximal proliferation rate of tumor cells increases.