Zhang, Wei, and Yong et al. describe a novel immunotherapy approach based on preparing extracellular microparticles (MPs) from an Ag-expressing macrophage (Mφ) cell line and loading the MPs with a M2-Mφ-targeting peptide and R848, resulting in R848@M2pep-MPsAg. In vitro, R848@M2pep-MPsAg reprogrammed M2-Mφ to an M1 inflammatory phenotype capable of antigen presentation and T cell activation. In an HCC model with alpha-fetoprotein as the Ag, and in a B16 melanoma model with OVA as Ag, R848@M2pep-MPsAg inhibited tumor growth (dependent on CD8+ and CD4+ T cells and Mφ), extended survival, reprogrammed the TME, and synergized with anti-PD-1.
Contributed by Ed Fritsch
ABSTRACT: The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8(+) T cells, especially stem-like CD8(+) T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs(AFP)) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs(AFP) target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs(AFP)-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8(+) T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8(+) T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8(+) T cell proliferation and differentiation to terminally exhausted CD8(+) T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
Author Info: (1) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (2) National Enginee
Author Info: (1) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (2) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (3) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China. (4) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (5) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (6) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (7) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (8) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (9) Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (10) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. (11) Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (13) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn. Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn. (14) National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn. Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
