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 using tumor-specific cytotoxic T lymphocytes (CTLs). Transforming growth factor (TGF)- signaling also contributes to immunosuppression in tumors via inactivation of CTL and activation of regulatory T cells. The combination of the CTL induction system and blocking system of TGF- signaling is attempted in this study using antigen-loaded pH-sensitive polysaccharide-modified liposome and liposome embedded SB505124: an inhibitor of TGF- type I receptor. 3-Methylglutarylated dextran (MGlu-Dex)-modified liposomes delivered the model antigenic protein, ovalbumin (OVA), into cytosol of dendritic cell line via pH-responsive membrane disruption. 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. Results show that 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. Results of the present study demonstrate that the combination of pH-sensitive polysaccharide-modified liposomes and SB-embedded liposomes is promising as an immunity-inducing system for cancer immunotherapy.

Liposome-based immunity-inducing systems for cancer immunotherapy

“…Combination delivery of IL-2 and inhibitor of TGF- type I receptor using poly(ethylene glycol)-modified liposomes encapsulating nanogel increase CD8-positive T cells and NK cells in tumor and cancer therapeutic effect was also improved strongly (Park et al, 2012). Combination of PEG-modified liposome embedded the inhibitor of TGF- type I receptor with pH-sensitive dextran-modified liposomes encapsulated antigenic proteins also strongly increased their immunotherapeutic effects by increased infiltration of CD8-positive T cells into tumor tissues (Yuba et al, 2017b). These reports indicate the importance of regulation of TGF- signaling in tumors for liposome-based immunity-inducing system.…”

Bioactive Nanoparticles for Cancer Immunotherapy

“…Recently, Yuba E et al studied the strong immunotherapeutic effect of pH-sensitive dextran liposomes modified with PEG as well as TGF-β 1 (transforming growth factor) receptors. The liposome delivery resulted in a high antitumor effect by the infiltration of CD8-positive cells to the tumor [74]. Yuba et al reported that liposomes modified with pH-sensitive polymers such as curdlan and mannan were used as bioactive polysaccharides.…”