Macrophage activation by a substituted pyrimido[5, 4-b]indole increases anti-cancer activity. (October 2019)

• Record Type: Journal Article
• Authors: Hardie, Joseph; Mas-Rosario, Javier A.; Ha, Siyoung; Rizzo, Erik M.; Farkas, Michelle E.
• Is Part Of: Pharmacological research. Volume 148(2019)
• Publication Date: 2019-10
• Subjects: CD47 cluster of differentiation 47 -- IL-4 interleukin 4 -- CS1 CCND3 subset 1 -- CSF1R colony stimulating factor receptor 1 -- MFEG8 milk fat globule-EGF factor 8 protein -- VEGF vascular endothelial growth factor -- SEAP secreted embryonic alkaline phosphatase -- LPS lipopolysaccharide -- IFN-γ interferon-γ; Inflammatory -- Immunotherapy -- Macrophage -- Adjuvant -- Cancer -- Phagocytosis; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104452
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: PBI1 can polarize undifferentiated M0 macrophages or re-program tumor-promoting M2 macrophages into the anti-tumor (M1) phenotype and enhance the phagocytosis of cancer cells. Abstract: Immunotherapy has become a promising new approach for cancer treatment due to the immune system's 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.