Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy

• Published in: Nature communications 2023-09, Vol.14 (1), p.5653-22, Article 5653
• Main Authors: Zhang, Xiaoqiong, Wei, Zhaohan, Yong, Tuying, Li, Shiyu, Bie, Nana, Li, Jianye, Li, Xin, Liu, Haojie, Xu, Hang, Yan, Yuchen, Zhang, Bixiang, Chen, Xiaoping, Yang, Xiangliang, Gan, Lu
• Format: Article
• Language: English
• Subjects: 13/109; 13/2; 13/21; 13/31; 13/51; 14/19; 14/3; 38/77; 631/67/580; 639/925/352/152; 639/925/352/2733; 692/4028/67/1059/2325; 82/1; 82/80; Animal models; Antibodies; Antigen-presenting cells; Antigens; Apoptosis; Cancer; CD8 antigen; Cell death; Cell differentiation; Cell proliferation; Cell-mediated immunity; Hepatocellular carcinoma; Humanities and Social Sciences; Immunological memory; Immunosurveillance; Immunotherapy; Inflammation; Liver cancer; Lymphocytes; Lymphocytes T; Macrophages; Melanoma; Memory cells; Microparticles; multidisciplinary; Ovalbumin; PD-1 protein; Phenotypes; Science; Science (multidisciplinary); Therapy; TLR7 protein; Toll-like receptors; Tumor microenvironment; Tumors; α-Fetoprotein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41438-9

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. Tumor associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment, including hepatocellular carcinoma (HCC). Here the authors show that macrophage-derived microparticles modified with a M2-like macrophage targeting peptide and loaded with the TLR7/8 agonist resiquimod reprogram TAMs from immunosuppressive to inflammatory, promoting anti-tumor immune responses in preclinical HCC models.