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

Xiaoqiong Zhang, Zhaohan Wei, Tuying Yong, Shiyu Li, Nana Bie, Jianye Li, Xin Li, Haojie Liu, Hang Xu, Yuchen Yan, Bixiang Zhang, Xiaoping Chen, Xiangliang Yang () and Lu Gan ()
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Xiaoqiong Zhang: Huazhong University of Science and Technology
Zhaohan Wei: Huazhong University of Science and Technology
Tuying Yong: Huazhong University of Science and Technology
Shiyu Li: Huazhong University of Science and Technology
Nana Bie: Huazhong University of Science and Technology
Jianye Li: Huazhong University of Science and Technology
Xin Li: Huazhong University of Science and Technology
Haojie Liu: Huazhong University of Science and Technology
Hang Xu: Huazhong University of Science and Technology
Yuchen Yan: Huazhong University of Science and Technology
Bixiang Zhang: Huazhong University of Science and Technology
Xiaoping Chen: Huazhong University of Science and Technology
Xiangliang Yang: Huazhong University of Science and Technology
Lu Gan: Huazhong University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-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.

Date: 2023
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DOI: 10.1038/s41467-023-41438-9

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