| Summary: | Xinghan Liu,1 Yujun Xu,1 Lijie Yin,1 Yayi Hou,1,2 Shuli Zhao3 1The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People’s Republic of China; 2Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, People’s Republic of China; 3General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of ChinaCorrespondence: Yayi HouThe State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People’s Republic of China, Tel/Fax +86-25-8968-8441Email yayihou@nju.edu.cnShuli ZhaoGeneral Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of China, Tel/Fax +86-25-8968-8441Email shulizhao79@163.comPurpose: 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. Mn2+ 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 MnCl2 (R-M@CS-PAA NPs) could exert an anti-tumor effect by regulating the function of immune cells.Methods: R-M@CS-PAA NPs were prepared, and their basic characteristics, anti-tumor effect, and potential mechanisms were explored both in vitro and in vivo.Results: R-M@CS-PAA NPs easily released MnCl2 and R848 at low pH. In B16F10 mouse melanoma model, R-M@CS-PAA NPs exerted the most significant anti-melanoma effect compared with the control group and CS-PAA NPs loaded with R848 or MnCl2 alone. FITC-labeled R-M@CS-PAA NPs were displayed to be accumulated at the tumor site. R-M@CS-PAA 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 R-M@CS-PAA NPs polarized macrophages into the M1 phenotype to inhibit the proliferation of B16F10 cells. R-M@CS-PAA NPs also enhanced the killing function of CD8+ T cells to B16F10 cells. Of note, R-M@CS-PAA 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 R-M@CS-PAA NPs is an effective therapeutic strategy against melanoma.Keywords: T cell, STING, NF-кB, antigen-presenting cell
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