Modeling tumour heterogeneity of PD-L1 expression in tumour progression and adaptive therapy.

ABSTRACT

Although PD-1/PD-L1 inhibitors show potent and durable anti-tumour effects in some refractory tumours, the response rate in overall patients is unsatisfactory, which in part due to the inherent heterogeneity of PD-L1. In order to establish an approach for predicting and estimating the dynamic alternation of PD-L1 heterogeneity during cancer progression and treatment, this study establishes a comprehensive modelling and computational framework based on a mathematical model of cancer cell evolution in the tumour-immune microenvironment, and in combination with epigenetic data and overall survival data of clinical patients from The Cancer Genome Atlas. Through PD-L1 heterogeneous virtual patients obtained by the computational framework, we explore the adaptive therapy of administering anti-PD-L1 according to the dynamic of PD-L1 state among cancer cells. Our results show that in contrast to the continuous maximum tolerated dose treatment, adaptive therapy is more effective for PD-L1 positive patients, in that it prolongs the survival of patients by administration of drugs at lower dosage.