Anti-CD122 antibody restores specific CD8⁺ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth

ABSTRACT

Nonalcoholic steatohepatitis (NASH) can lead to hepatocellular carcinoma (HCC). Although immunotherapy is used as first-line treatment for advanced HCC, the impact of NASH on anticancer immunity is only partially characterized. We assessed the tumor-specific T cell immune response in the context of NASH. In a mouse model of NASH, we observed an expansion of the CD44⁺CXCR6⁺PD-1⁺CD8⁺ T cells in the liver. After intra-hepatic injection of RIL-175-LV-OVA-GFP HCC cells, NASH mice had a higher percentage of peripheral OVA-specific CD8⁺ T cells than control mice, but these cells did not prevent HCC growth. In the tumor, the expression of PD-1 on OVA-specific CD44⁺CXCR6⁺CD8⁺ cells was higher in NASH mice suggesting lowered immune activity. Treating mice with an anti-CD122 antibody, which reduced the number of CXCR6⁺PD-1⁺ cells, we restored OVA-specific CD8 activity, and reduced HCC growth compared to untreated NASH mice. Human dataset confirmed that NASH-affected livers, NASH tissues adjacent to HCC and HCC in patients with NASH exhibited gene expression patterns supporting mouse observations. Our findings demonstrate the immune system fails to prevent HCC growth in NASH, primarily linked to a higher representation of CD44⁺CXCR6⁺PD-1⁺CD8⁺ T cells. Treatment with an anti-CD122 antibody reduces the number of these cells and prevents HCC growth.

KEYWORDS:

• Hepatocellular carcinoma
• immunotherapy
• nonalcoholic steatohepatitis

Acknowledgments

We thank the team of the Flow cytometry, Genomic and Histology core facilities, as well as the small animal preclinical imaging platform facility of the Faculty of Medicine (University of Geneva). We thank Dr Nicolas Goossens for his advice and Dr Beata Kusmider for her attentive proofreading.

Disclosure statement

The authors report there are no competing interests to declare.

Data repository

The datasets analyzed during the current study are available in the Gene Expression Omnibus repository https://www.ncbi.nlm.nih.gov/geo/. The data that support the findings of this study are openly available in Yareta - 10.26037/yareta:3527i5vapbcmlmt2kob4v2r4hi

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2184991

Additional information

Funding

This work was supported by the Swiss National Science Foundation (grant number 182471), the “Fondation Francis & Marie-France Minkoff “ and the Leenaards Foundation (grant number 5489).