Simulations of tumor growth and response to immunotherapy by coupling a spatial agent-based model with a whole-patient quantitative systems pharmacology model
Fig 8
Cell distribution and cell density at the IF under treatment.
Panel A: Spatial representation of cancer cell subtypes (left), CD8+ T cells subtypes, FoxP3+ T cells, and MDSCs (center), and all cells (right) in a section of a tumor slice. The IF region is depicted in pale turquoise. Slow tumor growth case (kC1,growth = 0.005 day-1) and R << 1 (R = 1/50). Panel B: 3D representation of CD8+ T cell and FoxP3+ T cell densities in the central tumor (CT; yellow), the invasive front (IF; red), and the normal tissue (N; green). Panel C: Average of CD8+ T cell and FoxP3+ T cell density profiles that are perpendicular to the IF. 95% confidence intervals are calculated upon the profile (grey areas). Two definitions of IF are introduced here and are indicated as vertical lines, blue: width wpathol=0.5 mm; red: width wpathol=1 mm. Panel D: Average of CD8+ T cell and FoxP3+ T cell density profiles along the IF. In panels C and D every row is a case with a different combination of ratios kC1,growth/kC,T1, kT1/kTreg, and the parameter Treg,max, where kC1,growth, kC,T1, kT1, kTreg, and Treg,max are the cancer cell growth rate, the rate of cancer cell death by T cells, the exhaustion rate of cytotoxic T cells by all cells that express PD-L1, the inhibition rate of cytotoxic T cells by regulatory T cells, and the maximal regulatory T cell density in the tumor, respectively. The spatial QSP algorithm calculated the evolution of a tumor slice starting from a fraction of a normal distribution of cancer cells. QSP model and ABM are coupled before reaching the point where T cells are recruited and also before the initial tumor diameter condition from the QSP model is met. Thus, no initial T cell spatial distribution is enforced. The figures here presented show cell distributions and densities 6 months after the initial tumor diameter condition is met with 3 mg/kg nivolumab administered every two weeks.