Computational Modeling to Determine the Effect of Phenotypic Heterogeneity in Tumors on the Collective Tumor–Immune Interactions

Abstract

Tumor immunotherapy aims to maintain or enhance the killing capability of CD8+ T cells to clear tumor cells. The tumor-immune interactions affect the function of CD8+ T cells. However, the effect of phenotype heterogeneity of a tumor mass on the collective tumor-immune interactions is insufficiently investigated. We developed the cellular-level computational model based on the principle of cellular Potts model to solve the case mentioned above. We considered how asymmetric division and glucose distribution jointly regulated the transient changes in the proportion of proliferating/quiescent tumor cells in a solid tumor mass. The evolution of a tumor mass in contact with T cells was explored and validated by comparing it with previous studies. Our modeling exhibited that proliferating/quiescent tumor cells, exhibiting distinct anti-apoptotic and suppressive behaviors, redistributed within the domain accompanied by the evolution of a tumor mass. Collectively, a tumor mass prone to a quiescent state weakened the collective suppressive functions of a tumor mass on cytotoxic T cells and triggered a decline of apoptosis of tumor cells. Although quiescent tumor cells did not sufficiently do their inhibitory functions, the possibility of long-term survival was improved due to their interior location within a mass. Overall, the proposed model provides a useful framework to investigate collective-targeted strategies for improving the efficiency of immunotherapy.