Studies on Peptide-Based Dual Gene Delivery System Targeting Tumor Associated Macrophage for Cancer Immunotherapy

Abstract

Cancer cells produce a pro-tumoral microenvironment that supports growth through secreting factors which educate immune cells to be immunosuppressive. Furthermore, the tumor microenvironment is involved in impaired angiogenesis. Tumor associated macrophages (TAMs) are types of immune cells in this tumor microenvironment, and play a role in the tumor growth inducing an inflammatory environment or angiogenesis. TAMs are classified into M2-type macrophages (M2 macrophage), showing anti-inflammatory characteristics. Cancer immunotherapy system using M2 macrophage-targeted dual gene delivery was developed after the fusion peptide which has a targetability to M2 macrophages in the tumor microenvironment. Oligoarginine was conjugated to peptide that can target the M2 macrophages (M2pep9R). RNA interference system against interferon regulatory factor 3 (siIRF3) and vascular endothelial growth factor (siVEGF) were constructed for dual gene therapy. Inhibition of PI3K/AKT signaling through siIRF3 resulted in repolarization of TAMs to inflammatory M1-type macrophages, following inflammatory environment. Therapeutic siVEGF led to a normalization of angiogenesis in the tumor environment. Dual delivery of siIRF3 and siVEGF showed inhibition of tumor growth. This study suggests a novel system of cancer immunotherapy using repolarization and manipulation of M2 type macrophages in the tumor microenvironment.