Figure 4.

Temporal variation in immune cell activity and dynamical model simulation in (a) combined as well as individual blockade of (b) PD-1 and (c) CTLA-4 pathways. Immune cell activity displays a much lower initial value in PD-1 blockade compared with the two other conditions. Contrary to PD-1 blockade, the decrease in cellular activity in CTLA-4 blockade entails a delay of several hours, while in the combined inhibition of the pathways, the cells remain active up to the last frames of the assays. Dynamical model parameters were inferred by fitting the model (blue curves) to immune activity changes derived from cell migration data (pink curves). Tumor–immune profiling of the spheroids and live/dead cell staining confer an initial value of $T_{t_0}\cong 22000\pm 30\%$ and final values of $T_f^{combo}\cong 14000\pm 15\%$, $T_f^{pd1}\cong 20000\pm 40\%$, and $T_f^{ctla4}\cong 13000\pm 35\%$ for the tumor cell population (yellow curves). Simulation results with the specified parameter set (σ = 0.00000022, ξ = 0.000000137, γ = 0.0000024, α = 0.0549, and β = 0.000016; all in a temporal unit of time step) show good agreement with the relative tumor-killing performance of anti-PD-1 and anti-CTLA-4 components according to cell death assessments in tumor spheroids. No unit is considered for cellular activity. Inset: Population-averaged persistence of immune cell migration in checkpoint inhibition experiments. The average values of the persistence parameter show moderate changes over time in the experiments. Error bar corresponds to standard error.