Team Approach to Integrating Mathematical and Biological Models to Target Myeloid-Derived Immune Cells in Glioblastoma

Objective: Integrate mathematical models of immunosuppressive glioblastoma (GBM) infiltrating myeloid cells with experimental data to predict therapeutic responses to combined chemokine receptor and immune checkpoint blockade.Methods: Orthotopic murine KR158-luc gliomas were established in mice. Subsequently, an anti-CD31 injection was administered to label the vasculature. Fluorescent imaging and quantification of anti-CD3 stained sections were performed on a range of tumor sizes to acquire vasculature, tumor, T cell, and myeloid cell densities. In parallel, a system of ordinary differential equations was formulated based on biological assumptions to evaluate the change over time of tumor cells, T cells, and infiltrating myeloid cells. The model was then refined and validated by experimental results.Results: Fluorescent imaging and quantification revealed a correlation between tumor size and abundance of myeloid cell populations in the tumor microenvironment. The density of these cell populations and vasculature remained constant as the tumors increased in size. Computer simulations of the mathematical model will predict tumor, myeloid, and T cell dynamics. These simulations will be particularly useful to understand myeloid cell dynamics, such as cell entry time into the tumor microenvironment. Parameter sensitivity analysis of the model will inform us of the biological processes driving these tumor-immune cell dynamics.