Group 1 ILC are dynamically regulated during in hepatocellular carcinogenesis

Introduction: In hepatocellular carcinoma (HCC), tumorigenesis, tumor progression and prognosis are highly dependent on the immune system and novel therapeutic approaches like immune checkpoint blockade (ICB) therefore aim to harness the anti-tumoral immune response. Despite good responses in some patients, inhibitory signals within the tumor microenvironment (TME) impede therapeutic success in many patients. Group 1 innate lymphoid cells (ILC), consisting of natural killer cells (NK cells) and tissue-resident ILC1, comprise up to 40% of the liver lymphocyte infiltrate and play a central role in liver pathologies and cancerogenesis. NK cells are potently cytotoxic and have been shown to play a protective role in HCC, whereas the exact role of ILC1 is still poorly defined. Both cell types, however, are major contributors to the local immune response and are targeted by ICB therapy. In order to improve immunotherapeutic success, it is crucial to understand how NK cells and ILC1 are regulated within the HCC TME.

Aims: We aim to investigate how the changing microenvironments during hepatocarcinogenesis affect group 1 ILC phenotype and functionality.

Methods: In a mouse model of liver carcinogenesis, group 1 ILC were analyzed longitudinally via multi-color flow cytometry, single-cell RNA-sequencing, ATAC-sequencing and functional assays. Additionally, group 1 ILC from HCC patients’ peripheral blood, tumor and liver tissues were characterized.

Results: Liver carcinogenesis is accompanied by significant changes in group 1 ILC composition, phenotype and functionality. Both NK cells and ILC1 were enriched in tumor-bearing livers. Unexpectedly, the TME had diverging effects on group 1 ILC with ILC1 displaying an activated phenotype and increased degranulation. Analysis of transcriptomic and epigenetic changes in tumor-associated group 1 ILC identified central pathways of immune modulation within the TME.

Conclusion: Using high dimensionality flow cytometry, functional assays and multi-omics, we identified diverging microenvironmental effects on group 1 ILC in HCC tissues. Our findings will contribute to a better understanding of how the TME shapes immune cell functions in HCC.

 

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Publication History

Article published online:
26 September 2024