The Effect of Combined Immunotherapy Using TLR7 Ligand, HIF-1α Inhibitor, and Chemotherapy in Mice Model of Colon Cancer

Abstract

Purpose Recently, chemoimmunotherapy has become a promising approach with remarkable therapeutic outcomes. In this study, we aimed to target HIF-1α as a reshaping of the immunosuppressive tumor microenvironment (TME) in combination with chemoimmunotherapy to enhance the antitumor response of the therapy. Materials/methods The HIF signaling pathway was suppressed in CT26 mouse colon cancer cells by using HIF-1α siRNA-loaded chitosan nanoparticles (NPs) both in vitro and in vivo. We assessed the synergistic effect of HIF-1α genetic silencing combined with oxaliplatin (OXA) and imiquimod (IMQ) on apoptosis, proliferation, tumor growth, and TME in mice colorectal cancer (CRC) models. Results CH/HIF-1α siRNA nanoparticles decreased the relative expression of HIF-1α gene and protein in cultured and tumor CT26 cells. Compared to other combined treatments, mice treated with IMQ as a TLR agonist and OXA (a first-line chemotherapy drug) and HIF-1α siRNA showed a significant reduction in tumor growth, which was associated with high levels of cytokines associated with cellular immunity. The triple combination treatment decreases genes and proteins expression levels of anti-apoptotic (Bcl-2) and cell proliferation (STAT3 and VEGF) and increases cytokines related to cellular immunity (IL12, IFN-γ) and pro-apoptotic (BAD, BAX). Furthermore, mice without HIF-1α siRNA treatment showed high tumor growth and high levels of immunosuppressive factors, indicating an immunosuppressive phenotype. Conclusions The data suggest that targeting HIF-1α represents a promising approach to augment the antitumor response of chemoimmunotherapy.