Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy

Yonghyun Lee (), Jongyoon Shinn, Cheng Xu, Hannah E. Dobson, Nouri Neamati and James J. Moon ()
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Yonghyun Lee: Ewha Womans University
Jongyoon Shinn: Ewha Womans University
Cheng Xu: University of Michigan
Hannah E. Dobson: University of Michigan
Nouri Neamati: University of Michigan
James J. Moon: University of Michigan

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

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40270-5

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