Abstract
Background
Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated.
Methods
Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing.
Results
The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells.
Conclusion
Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.
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Acknowledgment
This work was partly supported by JSPS KAKENHI grant numbers 19K09218 and 16K10574. We are grateful to Syuiti Sakaguti (Science Research Center, Yamaguchi University) for supporting us with the radioisotope experiment.
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Kimura, Y., Tsunedomi, R., Yoshimura, K. et al. Immune Evasion of Hepatoma Cancer Stem-Like Cells from Natural Killer Cells. Ann Surg Oncol 29, 7423–7433 (2022). https://doi.org/10.1245/s10434-022-12220-w
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DOI: https://doi.org/10.1245/s10434-022-12220-w