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<p>Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, arises from diverse etiologies that shape the tumor immune landscape, including the composition and function of innate lymphoid cells (ILCs). In this study, we integrated scRNA-seq, bulk RNA-seq, and CyTOF to profile ILCs from tumor and adjacent non-tumor liver tissues of 50 HCC patients with different etiologies (hepatitis B viral, HBV and non-viral, NV). ScRNA-seq revealed heterogenous ILC and NK clusters in non-tumor and tumor tissues. Notably, ILC1 could be subdivided into proliferative (ILC1<i>p</i>) and cytotoxic (ILC1<i>c</i>) phenotypes. ILC2 displayed classic type-2 immune traits with phenotypic heterogeneity, while ILC3 expressed key transcription factors and <i>IL18</i>. ILC subsets diverged significantly by disease etiology. In NV-HCC, ILC2s exhibited a pro-fibrotic and tumor-promoting signature with elevated <i>IL13</i>, <i>TGFB1</i>, and <i>AREG</i> expression. ILC1s in NV-HCC showed activated and cytotoxic phenotypes, whereas in HBV-HCC, they showed signs of exhaustion with increased <i>CD96</i> and <i>TIGIT</i>. ILC1 from NV-HCC also displayed enhanced IL-2/IL-15 signaling and interactions with CD8 + T cells via HLA-E, suggestive of potential antitumor crosstalk. While our single-cell cohort size was limited, necessitating validation in larger datasets, our study reveals etiology-associated differences in ILC phenotypes in HCC and provides insight into their potential roles in modulating immune responses within the tumor microenvironment.</p>

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Innate lymphoid cell heterogeneity and etiology-specific reprogramming in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Yun Hua Lee,
  • Samuel Chuah,
  • Wei Qiang Leow,
  • Sharifah N. Hazirah,
  • Martin Wasser,
  • Alexander Chung,
  • Brian K. P. Goh,
  • Pierce K. H. Chow,
  • Salvatore Albani,
  • Joycelyn Lee,
  • Tony K. H. Lim,
  • Yock Young Dan,
  • Seng Gee Lee,
  • David Tai,
  • Jinmiao Chen,
  • Haiyan Liu,
  • Valerie Chew

摘要

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, arises from diverse etiologies that shape the tumor immune landscape, including the composition and function of innate lymphoid cells (ILCs). In this study, we integrated scRNA-seq, bulk RNA-seq, and CyTOF to profile ILCs from tumor and adjacent non-tumor liver tissues of 50 HCC patients with different etiologies (hepatitis B viral, HBV and non-viral, NV). ScRNA-seq revealed heterogenous ILC and NK clusters in non-tumor and tumor tissues. Notably, ILC1 could be subdivided into proliferative (ILC1p) and cytotoxic (ILC1c) phenotypes. ILC2 displayed classic type-2 immune traits with phenotypic heterogeneity, while ILC3 expressed key transcription factors and IL18. ILC subsets diverged significantly by disease etiology. In NV-HCC, ILC2s exhibited a pro-fibrotic and tumor-promoting signature with elevated IL13, TGFB1, and AREG expression. ILC1s in NV-HCC showed activated and cytotoxic phenotypes, whereas in HBV-HCC, they showed signs of exhaustion with increased CD96 and TIGIT. ILC1 from NV-HCC also displayed enhanced IL-2/IL-15 signaling and interactions with CD8 + T cells via HLA-E, suggestive of potential antitumor crosstalk. While our single-cell cohort size was limited, necessitating validation in larger datasets, our study reveals etiology-associated differences in ILC phenotypes in HCC and provides insight into their potential roles in modulating immune responses within the tumor microenvironment.