Abstract
Understanding the human cytotoxic T lymphocyte (CTL) biology is crucial to develop novel strategies aiming at maximizing their lytic capacity against cancer cells. Here we introduce an agent-based model, calibrated on population-scale experimental data that allows quantifying human CTL per capita killing. Our model highlights higher individual CTL killing capacity at lower CTL densities and fits experimental data of human melanoma cell killing. The model allows extending the analysis over prolonged time frames, difficult to investigate experimentally, and reveals that initial high CTL densities hamper efficacy to control melanoma growth. Computational analysis forecasts that sequential addition of fresh CTL cohorts improves tumor growth control. In vivo experimental data, obtained in a mouse melanoma model, confirm this prediction. Taken together, our results unveil the impact that sequential adjustment of cellular densities has on enhancing CTL efficacy over long-term confrontation with tumor cells. In perspective, they can be instrumental to refine CTL-based therapeutic strategies aiming at controlling tumor growth.
Highlights
Various strategies are currently employed to potentiate human cytotoxic T lymphocyte (CTL)-mediated immune responses in cancer patients with the goal of impairing tumor progressions
Human CTL were conjugated with target cells pulsed with the antigenic peptide or left unpulsed
In line with our previously reported data[5,10,21], we observed that, while killing of conventional target cells could be detected even at very low E/T ratios (
Summary
Various strategies are currently employed to potentiate human CTL-mediated immune responses in cancer patients with the goal of impairing tumor progressions. Gaining in vitro data on human CTL per capita killing requires visualization of a large number of individual CTL/target cell interactions using time-lapse microscopy optimized for single cell inspection[10,11,12]. This approach is technically challenging and complex to extrapolate to clinical settings. To overcome such a technical bottleneck, we designed an agent-based model, calibrated on experimental measurements, which accurately reproduces human CTL/tumor cell interactions taking place within the culture dish This in silico approach allows to perform data analysis and modeling of in vitro results obtained at the population level and to extrapolate them to the single cell level. In the present study aiming at defining CTL per capita killing, we focus our investigation on the events occurring at the contact site between CTL and target cells during the very rapid process of lethal hit delivery[18,19,20]
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