Abstract 2722: Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization

Abstract Tumor-associated macrophages (TAMs) are M2-polarized protumoral macrophages, whereas inflammatory macrophages are M1-polarized antitumoral macrophages. Interleukin-4 receptor (IL-4R) is expressed in M2 macrophages at higher levels than M1 macrophages. In this study, we aimed to inhibit tumor growth using M1 macrophage-derived exosomes engineered to target IL-4R and reprogram TAMs into M1 macrophages. M1 exosomes were transfected with NF-κB p50 siRNA and miR-511-3p as cargoes to enhance M1 polarization (Exo-si/mi) and surface-modified with IL4RPep-1, an IL-4R-binding peptide, to target IL-4R of M2 macrophages (IL4R-Exo-si/mi). The engineered exosomes showed sizes similar with parental exosomes, and IL4RPep-1 was retained on the exosomes and not degraded in the presence of serum up to 24 h. IL-4R-targeted exosomes were internalized into M2 macrophages and delivered cargoes through IL-4R more efficiently than untargeted exosomes. Whole-body fluorescence imaging showed that IL-4R-targeted exosomes homed to tumors at higher levels than to liver unlike to untargeted exosomes. Intravenous administration of IL4R-Exo-si/mi decreased the levels of M2 markers and immune-suppressive cells including TAMs, while increasing the levels of M1 markers and immune-stimulatory cells including M1 macrophages in tumor and spleen and subsequently inhibited tumor growth more efficiently than Exo-si/mi as well as M1 exosomes. These results suggest that IL-R-targeted exosomes carrying NF-κB p50 siRNA and miR-511-3p inhibit tumor growth by reprogramming TAMs into M1 macrophages and increasing anti-tumor immunity and hold a potential for caner immunotherapy. Citation Format: Byungheon Lee, Gowri Rangaswamy Gunassekaran. Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2722.