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  3. 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

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

  • Nat Commun. 2023 Sep 13;14(1):5653. doi: 10.1038/s41467-023-41438-9.
Xiaoqiong Zhang # 1,  Zhaohan Wei # 1,  Tuying Yong # 1 2 3 4,  Shiyu Li 1,  Nana Bie 1,  Jianye Li 1,  Xin Li 1,  Haojie Liu 1,  Hang Xu 2,  Yuchen Yan 1,  Bixiang Zhang 5,  Xiaoping Chen 5,  Xiangliang Yang 6 7 8 9,  Lu Gan 10 11 12 13
Affiliations

Affiliations

  • 1 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, 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. yangxl@mail.hust.edu.cn.
  • 7 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.
  • 8 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn.
  • 9 Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China. yangxl@mail.hust.edu.cn.
  • 10 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.
  • 11 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.
  • 12 Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
  • 13 Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, China. lugan@mail.hust.edu.cn.
  • # Contributed equally.
PMID: 37704614 DOI: 10.1038/s41467-023-41438-9
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.

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