Myeloid-derived suppressor cell dynamics control outcomes in the metastatic niche

Abstract

Myeloid-derived suppressor cells (MDSCs) play a prominent and rising role in the tumor microenvironment. An understanding of the tumor-MDSC interactions that influence disease progression is critical, and currently lacking. To address this, we developed a mathematical model of metastatic growth and progression in immune-rich tumor microenvironments. We model the tumor-immune dynamics with stochastic delay differential equations, and study the impact of delays in MDSC activation/recruitment on tumor growth outcomes. We find when the circulating level of MDSCs is low, the MDSC delay has a pronounced impact on the probability of new metastatic establishment: blocking MDSC recruitment can reduce the probability of metastasis by as much as 50%. We also quantify the extent to which decreasing the immuno-suppressive capability of the MDSCs impacts the probability that a new metastasis will persist or grow. In order to quantify patient-specific MDSC dynamics under different conditions we fit individual tumors treated with immune checkpoint inhibitors to the tumor-MDSC model via Bayesian parameter inference. We reveal that control of the inhibition rate of natural killer cells by MDSCs has a larger influence on tumor outcomes than controlling the tumor growth rate directly. Posterior classification of tumor outcomes demonstrates that incorporating knowledge of the MDSC responses improves predictive accuracy from 63% to 82%. Our results illustrate the importance of MDSC dynamics in the tumor microenvironment and predict interventions that may shift environments towards a less immune-suppressed state. We argue that there is a pressing need to more often consider MDSCs in analyses of tumor microenvironments.