1. Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma.
- Author
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Teo JMN, Chen Z, Chen W, Tan RJY, Cao Q, Chu Y, Ma D, Chen L, Yu H, Lam KH, Lee TKW, Chakarov S, Becher B, Zhang N, Li Z, Ma S, Xue R, and Ling GS
- Subjects
- Humans, Animals, Mice, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Cell Line, Tumor, Cell Proliferation, Linoleic Acid metabolism, Mice, Inbred C57BL, Male, Immunotherapy methods, Transforming Growth Factor beta metabolism, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular pathology, Liver Neoplasms immunology, Liver Neoplasms pathology, Neutrophils immunology, Neutrophils metabolism, Tumor Microenvironment immunology
- Abstract
Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development., (© 2024 Teo et al.)
- Published
- 2025
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