Chitosan-Poly(Acrylic Acid) Nanoparticles Loaded with R848 and MnCl2 Inhibit Melanoma via Regulating Macrophage Polarization and Dendritic Cell Maturation
Xinghan Liu, Yujun Xu, Lijie Yin, Yayi Hou, Shuli Zhao
Abstract
Purpose: Since immune cells in the tumor microenvironment (TME) can affect the development and progression of tumors, strategies modulating immune cells are considered to have an important therapeutic effect. As a TLR7/8 agonist, R848 effectively activates the innate immune cells to exert an anti-tumor effect. Mn 2+ has been reported to strongly promote the maturation of antigen-presenting cells (APCs), thereby enhancing the cytotoxicity of CD8 + T cells. Thus, we tried to investigate whether chitosan-poly(acrylic acid) nanoparticles (CS-PAA NPs) loaded with R848 and MnCl 2 ( [email protected] NPs) could exert an anti-tumor effect by regulating the function of immune cells. Methods: [email protected] NPs were prepared, and their basic characteristics, anti-tumor effect, and potential mechanisms were explored both in vitro and in vivo. Results: [email protected] NPs easily released MnCl 2 and R848 at low pH. In B16F10 mouse melanoma model, [email protected] NPs exerted the most significant anti-melanoma effect compared with the control group and CS-PAA NPs loaded with R848 or MnCl 2 alone. FITC-labeled [email protected] NPs were displayed to be accumulated at the tumor site. [email protected] NPs significantly increased the infiltration of M1 macrophages and CD8 + T cells but reduced the number of suppressive immune cells in the TME. Moreover, in vitro experiments showed that [email protected] NPs polarized macrophages into the M1 phenotype to inhibit the proliferation of B16F10 cells. [email protected] NPs also enhanced the killing function of CD8 + T cells to B16F10 cells. Of note, [email protected] NPs not only promoted the maturation of APCs such as dendritic cells and macrophages by STING and NF-кB pathways, but also enhanced the ability of dendritic cells to present ovalbumin to OT-I CD8 + T cells to enhance the cytotoxicity of OT-I CD8 + T cells to ovalbumin-expressing B16F10 cells. Conclusion: These data indicate that the administration of [email protected] NPs is an effective therapeutic strategy against melanoma. Keywords: T cell, STING, NF-кB, antigen-presenting cell