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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/729459v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@1aed309org.highwire.dtl.DTLVardef@a11696org.highwire.dtl.DTLVardef@1d1d74dorg.highwire.dtl.DTLVardef@18e2c3f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 0C_FLOATNO / Graphical Abstract: Illustration of the SHOCO Model. (A) Overview of the components used in creating SHOCOs and the complex tumor microenvironment they replicate. Epithelial cells (pink), CAFs (red), CD8 T cell (blue), CD4 T cell (green). Characteristics of SHOCOs: (B) Emphasizing the role of CAFs in contracting and creating a denser microenvironment. (C) CAFs act as a physical barrier, preventing CD8 T cells from reaching tumor niches. (D) SHOCOs maintain a substantial myeloid population (violet) capable of performing antigen presentation. (E) T cells within SHOCOs mount an anti-tumor cytotoxic immune response as a result of immunotherapy. Granzymes (orange), cleaved Caspase-3/7 (yellow). C_FIG