Abstract
Purpose
High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research.
Methods
SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF).
Results
We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models.
Conclusions
This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank the Public Technology Service Center Fujian Medical University for their help and technical support.
Funding
This work was supported by the Key Project of Fujian Provincial Natural Science Foundation (2022J02039), the Joint Funds for the Innovation of Science and Technology, Fujian Province (2021Y9067), the National Natural Science Foundation of China (82173167), and the High-Level Medical Care Construction Foundation of Fujian Province ([2021]76).
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Conception and design: ZW, BP and LS. Development of methodology: HY, YY and XW. Data curation: JQ and XZ. Writing, review and/or revision of the manuscript: ZW, BP and LS. Study supervision: NT.
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Wang, Z., Pan, B., Su, L. et al. SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma. Cell Oncol. 47, 513–532 (2024). https://doi.org/10.1007/s13402-023-00880-z
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DOI: https://doi.org/10.1007/s13402-023-00880-z