Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

Any disruption of the lymphatic system due to trauma or injury can lead to edema. There is no effective cure for lymphedema, partly because predictive knowledge of lymphatic system reactions to interventions is lacking. A well-developed model of the system could greatly improve our understanding of its function. Lymphangions, defined as the vessel segment between two valves, are the individual pumping units. Based on our previous lumped-parameter model of a chain of lymphangions, this study aimed to identify the parameters that affect the system output the most using a sensitivity analysis. The system was highly sensitive to minimum valve resistance, such that variations in this parameter caused an order-of-magnitude change in time-average flow rate for certain values of imposed pressure difference. Average flow rate doubled when contraction frequency was increased within its physiological range. Optimum lymphangion length was found to be some 13-14.5 diameters. A peak of time-average flow rate occurred when transmural pressure was such that the pressure-diameter loop for active contractions was centered near maximum passive vessel compliance. Increasing the number of lymphangions in the chain improved the pumping in the presence of larger adverse pressure differences. For a given pressure difference, the optimal number of lymphangions increased with the total vessel length. These results indicate that further experiments to estimate valve resistance more accurately are necessary. The existence of an optimal value of transmural pressure may provide additional guidelines for increasing pumping in areas affected by edema.

Many tissues exhibit subatmospheric interstitial pressures under normal physiologic conditions. The mechanisms by which the lymphatic system extracts fluid from these tissues against the overall pressure gradient are unknown. We address this important physiologic issue by combining experimental measurements of contractile function and pressure generation with a previously validated mathematical model. We provide definitive evidence for the existence of ‘suction pressure’ in collecting lymphatic vessels, which manifests as a transient drop in pressure downstream of the inlet valve following contraction. This suction opens the inlet valve and is required for filling in the presence of low upstream pressure. Positive transmural pressure is required for this suction, providing the energy required to reopen the vessel. Alternatively, external vessel tethering can serve the same purpose when the transmural pressure is negative. Suction is transmitted upstream, allowing fluid to be drawn in through initial lymphatics. Because suction plays a major role in fluid entry to the lymphatics and is affected by interstitial pressure, our results introduce the phenomenon as another important factor to consider in the study of lymphoedema and its treatment.

The lymphatic system is an open-ended network of vessels that run in parallel to the blood circulation system. These vessels are present in almost all of the tissues of the body to remove excess fluid. Similar to blood vessels, lymphatic vessels are found in branched arrangements. Due to the complexity of experiments on lymphatic networks and the difficulty to control the important functional parameters in these setups, computational modeling becomes an effective and essential means of understanding lymphatic network pumping dynamics. Here we aimed to determine the effect of pumping coordination in branched network structures on the regulation of lymph flow. Lymphatic vessel networks were created by building upon our previous lumped-parameter model of lymphangions in series. In our network model, each vessel is itself divided into multiple lymphangions by lymphatic valves that help maintain forward flow. Vessel junctions are modeled by equating the pressures and balancing mass flows. Our results demonstrated that a 1.5 s rest-period between contractions optimizes the flow rate. A time delay between contractions of lymphangions at the junction of branches provided an advantage over synchronous pumping, but additional time delays within individual vessels only increased the flow rate for adverse pressure differences greater than 10.5 cmH2O. Additionally, we quantified the pumping capability of the system under increasing levels of steady transmural pressure and outflow pressure for different network sizes. We observed that peak flow rates normally occurred under transmural pressures between 2 to 4 cmH2O (for multiple pressure differences and network sizes). Networks with 10 lymphangions per vessel had the highest pumping capability under a wide range of adverse pressure differences. For favorable pressure differences, pumping was more efficient with fewer lymphangions. These findings are valuable for translating experimental measurements from the single lymphangion level to tissue and organ scales.