Mathematical model predicts tumor control patterns induced by fast and slow cytotoxic T lymphocyte killing mechanisms

Abstract

AbstractImmunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells. To determine the critical factors affecting responses to ICIs, we construct an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD-L1 immune checkpoint. Specifically, we identify important aspects of the tumor-immune landscape that affect tumor size and composition in the short and long term. We also generate a virtual cohort of mice with diverse tumor and immune attributes to simulate the outcomes of immune checkpoint blockade in a heterogeneous population. By identifying key tumor and immune characteristics associated with tumor elimination, dormancy, and escape, we predict which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy.