Bioprinted Multicomponent Hydrogel Co-culture Tumor-Immune Model for Assessing and Simulating Tumor-Infiltrated Lymphocyte Migration and Functional Activation

The immune response against a tumor is characterizedby the interplayamong components of the immune system and neoplastic cells. Here,we bioprinted a model with two distinct regions containing gastriccancer patient-derived organoids (PDOs) and tumor-infiltrated lymphocytes(TILs). The initial cellular distribution allows for the longitudinalstudy of TIL migratory patterns concurrently with multiplexed cytokineanalysis. The chemical properties of the bioink were designed to presentphysical barriers that immune T-cells must breech during infiltrationand migration toward a tumor with the use of an alginate, gelatin,and basal membrane mix. TIL activity, degranulation, and regulationof proteolytic activity reveal insights into the time-dependent biochemicaldynamics. Regulation of the sFas and sFas-ligand present on PDOs andTILs, respectively, and the perforin and granzyme longitudinal secretionconfirms TIL activation when encountering PDO formations. TIL migratoryprofiles were used to create a deterministic reaction-advectiondiffusion model. The simulation provides insights that decouple passivefrom active cell migration mechanisms. The mechanisms used by TILsand other adoptive cell therapeutics as they infiltrate the tumorbarrier are poorly understood. This study presents a pre-screeningstrategy for immune cells where motility and activation across ECMenvironments are crucial indicators of cellular fitness.