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Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy

Author

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  • Yonghyun Lee

    (Ewha Womans University
    Ewha Womans University
    University of Michigan
    University of Michigan)

  • Jongyoon Shinn

    (Ewha Womans University
    Ewha Womans University)

  • Cheng Xu

    (University of Michigan
    University of Michigan)

  • Hannah E. Dobson

    (University of Michigan
    University of Michigan)

  • Nouri Neamati

    (University of Michigan)

  • James J. Moon

    (University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

Abstract

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.

Suggested Citation

  • Yonghyun Lee & Jongyoon Shinn & Cheng Xu & Hannah E. Dobson & Nouri Neamati & James J. Moon, 2023. "Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40270-5
    DOI: 10.1038/s41467-023-40270-5
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    1. Sydney R. Gordon & Roy L. Maute & Ben W. Dulken & Gregor Hutter & Benson M. George & Melissa N. McCracken & Rohit Gupta & Jonathan M. Tsai & Rahul Sinha & Daniel Corey & Aaron M. Ring & Andrew J. Conn, 2017. "PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity," Nature, Nature, vol. 545(7655), pages 495-499, May.
    2. Olivier De Henau & Matthew Rausch & David Winkler & Luis Felipe Campesato & Cailian Liu & Daniel Hirschhorn Cymerman & Sadna Budhu & Arnab Ghosh & Melissa Pink & Jeremy Tchaicha & Mark Douglas & Thoma, 2016. "Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells," Nature, Nature, vol. 539(7629), pages 443-447, November.
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