Synergetic Functional Nanocomposites Enhance Immunotherapy in Solid Tumors by Remodeling the Immunoenvironment.

Linnan Yang,Rongrong Zhu,Ang Li,Kun Li,Longpo Zheng,Shilong Wang,Jing Sun,Qiang Liu,Jiahui Hua,Qiannan Yang

doi:10.1002/advs.201802012

Abstract

Checkpoint blockade immunotherapy has demonstrated significant clinical success in various malignant tumors. However, the therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM). In this study, a functional nanomaterial, layered double hydroxides (LDHs), carrying specific functional miR155 is developed to modulate ITM by synergistically repolarizing tumor associated macrophages (TAMs) to M1 subtype. LDH nanoparticles loaded with miR155 (LDH@155) exhibit superior ability in cellular uptake by murine macrophages, miR escape into the cytoplasm and TAMs specific delivery when introtumoral administration. Meanwhile, upon exposure to LDH@155, TAMs are significantly skewed to M1 subtype, which markedly inhibits myeloid‐derived suppressor cells (MDSCs) formation and stimulates T‐lymphocytes to secrete more interferon‐γ (IFN‐γ) cytokines in vitro. Introtumoral administration of LDH@155 reduces the percentage of TAMs and MDSCs in the tumor and elevates CD4+ and CD8+ T cell infiltration and activation, which can promote therapeutic efficiency of α‐PD‐1 antibody immunotherapy. Furthermore, it is found that LDH@155 significantly decreases the expression level of phosphorylated STAT3 and ERK1/2 and activates NF‐κB expression in TAMs, indicating that the STAT3, ERK1/2, and NF‐κB signaling pathways may involve in LDH@155‐induced macrophage polarization. Overall, the results suggest that LDH@155 nanoparticles may, in the future, function as a promising agent for cancer combinational immunotherapy.

Highlights

Introduction success in various malignant tumorsthe therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM)
The results suggest that layered double hydroxides (LDHs)@155 nanoparticles may, in the future, function as a Numerous findings suggest that tumors recruit a constant influx of M2 subtype tumor associated macrophages (TAMs) in solid tumor[10] and a high TAM density positively correlates with poor prognosis in many human cancers.[11,12]
Previous studies have shown that SOCS1-STAT3-NF-κB and ERK1/2 signaling pathways participated in macrophages activation induced by miR155.[54]. Consistent with the above research, our present study revealed that STAT3 and ERK1/2 phosphorylated signal pathways were remarkable inhibited by loaded with miR155 (LDH@155) in TAMs repolarization

Summary

Introduction

The therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM). Combating specific functional miR155 is developed to modulate ITM by synergistically repolarizing tumor associated macrophages (TAMs) to M1 subtype. Upon solid tumors still remains an enormous challenge because of the immunosuppressive tumor microenvironment (ITM), which hinders antitumor immunity and promotes cancer progression.[4]. Effective antitumor immunity in tumor environexposure to LDH@155, TAMs are significantly skewed to M1 subtype, which markedly inhibits myeloid-derived suppressor cells (MDSCs) formation and stimulates T-lymphocytes to secrete more interferon-γ (IFN-γ ) cytokines in vitro. Introtumoral administration of LDH@155 reduces the percentage of TAMs and MDSCs in the tumor and elevates CD4+ and CD8+ T cell infiltration and activation, which can promote therapeutic efficiency of α-PD-1 antibody immunotherapy

Objectives

Results

Conclusion