Role of senescent tumor cells in building a cytokine shield in the tumor microenvironment: mathematical modeling.

Abstract

Cellular senescence can induce dual effects (promotion or inhibition) on cancer progression. While immune cells naturally respond and migrate toward various chemotactic sources from the tumor mass, various factors including senescent tumor cells (STCs) in the tumor microenvironment may affect this chemotactic movement. In this work, we investigate the mutual interactions between the tumor cells and the immune cells that either inhibit or facilitate tumor growth by developing a mathematical model that consists of taxis-reaction-diffusion equations and receptor kinetics for the key players in the interaction network. We apply a mathematical model to a transwell Boyden chamber invasion assay used in the experiments to illustrate that STCs can play a pivotal role in negating immune attack through tight regulation of intra- and extra-cellular signaling molecules. In particular, we show that senescent tumor cells in cell cycle arrest can block intratumoral infiltration of CD8+ T cells by secreting a high level of CXCL12, which leads to significant reduction its receptors, CXCR4, on T cells, and thus impaired chemotaxis. The predictions of nonlinear responses to CXCL12 were in good agreement with experimental data. We tested several hypotheses on immune-tumor interactions under various biochemical conditions in the tumor microenvironment and developed new concepts for anti-tumor strategies targeting senescence induced immune impairment.