Macrophage Activation by a Substituted PyrimidoIndole Increases Anti-Cancer Activity

Immunotherapy has become a promising new approach for cancer treatment due to the immune systems ability to remove tumors in a safe and specific manner. Many tumors express anti-inflammatory factors that deactivate the local immune response or recruit peripheral macrophages into pro-tumor roles. Because of this, effective and specific ways of activating macrophages into anti-tumor phenotypes is highly desirable for immunotherapy purposes. Here, the use of a small molecule TLR agonist as a macrophage activator for anti-cancer therapy is reported. This compound, referred to as PBI1, demonstrated unique activation characteristics and expression patterns compared to treatment with LPS, through activation of TLR4. Furthermore, PBI1 treatment resulted in anti-tumor immune behavior, enhancing macrophage phagocytic efficiency five-fold versus non-treated macrophages. Additive effects were observed via use of a complementary strategy (anti-CD47 antibody), resulting in [~]10-fold enhancement of phagocytosis, suggesting this small molecule approach could be used in conjunction with other therapeutics.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC=\"FIGDIR/small/581710_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (26K):\norg.highwire.dtl.DTLVardef@1c4aa23org.highwire.dtl.DTLVardef@7e1928org.highwire.dtl.DTLVardef@a5be7borg.highwire.dtl.DTLVardef@17c9d5e_HPS_FORMAT_FIGEXP M_FIG C_FIG