Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription

Area of Science:

• Oncology
• Immunology
• Metabolism

Background:

• Immunotherapy responsiveness is influenced by metabolic factors, but these are not fully understood.
• Hepatocellular carcinoma (HCC) patients treated with immune checkpoint blockade (ICB) show variable responses.
• Identifying metabolic determinants of ICB efficacy is crucial for improving cancer treatment.

Purpose of the Study:

• To investigate the role of ketone body metabolism in HCC response to ICB.
• To elucidate the molecular mechanisms linking metabolism to immunotherapy resistance.
• To identify potential therapeutic targets for enhancing ICB efficacy.

Main Methods:

• Multiomics analysis of tumor biopsies from HCC patients undergoing ICB.
• Investigation of OXCT1 expression, β-hydroxybutyrate (BHB) levels, and their correlation with ICB efficacy.
• Mechanistic studies involving glucose deprivation, AMPK activation, OXCT1 phosphorylation, and nuclear translocation.
• Analysis of OXCT1-IRF1 interaction and its effect on immune gene transcription.

Main Results:

• High OXCT1 expression correlated with poor ICB response, while BHB showed an inverse correlation.
• Glucose deprivation induced AMPK-mediated OXCT1 phosphorylation and nuclear translocation.
• Nuclear OXCT1, with IRF1, suppressed immune gene transcription by consuming BHB.
• Targeting the AMPK-OXCT1-IRF1 axis sensitized tumors to ICB, especially with a ketogenic diet.

Conclusions:

• A novel mechanism reveals nuclear OXCT1's role in linking ketone body metabolism to immunotherapy resistance in HCC.
• The AMPK-OXCT1-IRF1 axis represents a potential therapeutic target to overcome ICB resistance.
• Ketogenic diet combined with targeting this axis may enhance ICB efficacy in liver cancer.