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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

Author

Listed:
  • Xiaoqiong Zhang

    (Huazhong University of Science and Technology)

  • Zhaohan Wei

    (Huazhong University of Science and Technology)

  • Tuying Yong

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    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
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Lu Gan

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

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.

Suggested Citation

  • 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 & Lu Gan, 2023. "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," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41438-9
    DOI: 10.1038/s41467-023-41438-9
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    4. Zhaohan Wei & Xiaoqiong Zhang & Tuying Yong & Nana Bie & Guiting Zhan & Xin Li & Qingle Liang & Jianye Li & Jingjing Yu & Gang Huang & Yuchen Yan & Zelong Zhang & Bixiang Zhang & Lu Gan & Bo Huang & X, 2021. "Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
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