High-throughput approaches to discover novel immunomodulatory agents for cancer

Abstract

The clinical success of immunomodulatory thalidomide derivatives has renewed the general interest in immunomodulatory anticancer compounds and prompted us to develop a high-throughput system to quantify immune effector-cell activity. We documented that the interaction between cancer cells, their stroma, anticancer agents and cells from the innate system are critical for determining the response of tumors to immunomodulatory strategies.

Figure 1. Description of the compartment-specific bioluminescence (CS-BLI) platform for antitumor immunity screening. Luciferase-positive tumor cells are mixed in culture with interleukin-2 (IL-2)-stimulated peripheral blood mononuclear cells (PBMCs). High-throughput screening for specific antitumor activity in the presence and absence of immune-effector cells is shown for ~100 small molecule inhibitors. Direct antitumor activity (black) of a given compound was compared with its modulation of antitumor effector activity (green). Direct activity is normalized to the untreated controls, whereas the effector cell-mediated activity is normalized to control conditions including the drug but not effector cells. Effector cell-mediated data points (green) falling below the direct killing values (black) represent compounds that enhance antitumor immunity.