Potentiation of cancer immunity-inducing effect by pH-sensitive polysaccharide-modified liposomes with combination of TGF-β type I receptor inhibitor-embedded liposomes

Abstract

Recent success of immune checkpoint inhibitors has revealed that canceling of immunosuppression in tumor microenvironments is crucially important to achieve effective cancer immunotherapy via tumor-specific cytotoxic T lymphocytes (CTLs). Transforming growth factor (TGF)-beta signaling also contributes to immunosuppression in tumors via inactivation of CTL and activation of regulatory T cells. The combination of CTL induction system and blocking system of TGF-beta signaling is attempted in this study using antigen-loaded pH-sensitive polysaccharide-modified liposome and liposome embedded SB505124: an inhibitor of TGF-beta type I receptor. 3-Methylglutarylated dextran (MGlu-Dex)-modified liposomes delivered model antigenic protein, ovalbumin (OVA) into cytosol of dendritic cell line via pH-responsive membrane disruption and subcutaneous administration of these liposomes induced the regression of OVA-expressing tumor in mice. Additional administration of SB505124-embedded liposomes improved antitumor effects and survival in mice. Especially, intravenous administration of SB505124-embedded liposomes promoted the infiltration of CTL to tumor tissues significantly compared with single administration of MGlu-Dex-modified liposomes, leading to strong immunotherapeutic effects. Therefore, the combination of pH-sensitive polysaccharide-modified liposomes and SB-embedded liposomes is promising as an immunity-inducing system for cancer immunotherapy.