Organoid-based colorectal tumor microenvironment model for immuno-oncology research

The development of cancer immunotherapies is hindered by the lack of human-relevant models that accurately translate to patient outcomes. We combine patient-derived colorectal tumor organoids (PDOs) and cancer-associated fibroblasts (CAFs) into floating extracellular matrix drops to form miniature colorectal tumors. These SHaking Organoid COcultures (SHOCOs) maintain immune cells in numbers, states and functional interactions that are more physiologically accurate than traditional PDO-based co-culture models. Immunocompetent SHOCOs treated with T-cell bispecific antibodies exhibited a robust anti-tumor response, in a concentration- and duration of treatment-dependent manner. By varying the stromal content, we found that fibroblasts present a physical barrier that hinders intratumoral T-cell infiltration. We also demonstrate that tumor-associated stroma can be exploited therapeutically in potentiating anti-tumor immune responses. SHOCOs could aid the battle against cancer both by providing fundamental insights into immune and stromal tumor biology, and by catalyzing the discovery of novel therapeutic approaches.