(329e) Modeling the Impact of Heterogeneity in the Early Tumor-Immune Response

Before a tumor can progress to a detectable size, it first must develop ways to evade removal by the immune system. To do this, the tumor creates a favorable tumor microenvironment (TME) that suppresses some immune cells and corrupts others into a tumor-promoting state. Due to local pockets of diffusible factors and phenotypic differences between cells, the TME can exhibit high amounts of heterogeneity, both extracellular and intracellular. As it is difficult to assess this heterogeneity with in vivo or in vitro experiments, computational models can be used to interrogate the TME system in detail and provide new insights.

Here, we investigate the effects of phenotypic differences among multiple cell types in the TME. We model cancer cells, macrophages, and T cells. Using an agent-based model, we simulate the interactions between these three cell types, along with several diffusible factors present in the TME. Importantly, we model the behavior of individual cells, to examine how differences at the cellular level compound into differences at the population level. In addition, to produce more physiologically relevant scenarios, we utilize mechanistic models of intracellular signaaling for some key pathways related to the immune response. The dynamics of these intracellular signaling responses determine how the cell will behave. Finally, we incorporate heterogeneity in three ways: allowing phenotypic parameters to vary between cells of the same type, varying the xpressions of proteins in the intracellular signaling networks from cell to cell, and varying the levels of extraceullar stimuli. With our model, we are able to examine the ffects of various types of heterogeneity on the initial immune response to cancer growth, with and without various macrophage-based treatment strategies. Altogether, we gain a better understanding of the complexities of the TME.