Journal Article

Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy

Dobson, Hannah E., Lee, Yonghyun, Moon, James J., Xu, Cheng, Shinn, Jongyoon, Neamati, Nouri

2023

Overview

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 CD44 hi 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. Immunosuppressive tumour immune microenvironments (TME) limit the success of immune checkpoint blockade (ICD). Here, the authors develop a hyaluronic acid-bilirubin nanoparticle (HABN) capable of inducing immunogenic cell death in tumour cells and altering the TME, resulting in increased sensitivity to ICB (anti-PD-L1) in preclinical models of colorectal cancer and breast cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/34 / 631/250/251 / 639/166/985 / 639/925/352/152 / 64/60 / Apoptosis / Bilirubin / Breast cancer / Cancer / Cancer immunotherapy / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - metabolism / Cell death / Cell Line, Tumor / Chemotherapy / Colorectal cancer / Colorectal carcinoma / Cytokine Receptor gp130 / Glycoprotein gp130 / Humanities and Social Sciences / Humans / Hyaluronic acid / Hyaluronic Acid - pharmacology / Immune response / Immune system / Immunogenicity / Immunosuppression / Immunotherapy / Interleukin 6 / Lymphocytes T / Macrophages / Microenvironments / multidisciplinary / Myeloid cells / Nanomedicine / Nanoparticles / Nanotechnology / Neoplasms - drug therapy / Neoplasms - metabolism / PD-L1 protein / Phenotypes / Science / Science (multidisciplinary) / Stat3 protein / Suppressor cells / Tumor cells / Tumor Microenvironment / Tumors