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Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in
Junnan Liang1,2,3, Jingyu Liao1,2, Ruizhi Chang1,2
1Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.
Abstract:
The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell-derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti-PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti-PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.
Insights
The E3 ubiquitin ligase Riplet is silenced in liver cancer, promoting T cell exhaustion and immunotherapy resistance. Restoring Riplet or inhibiting fatty acid synthase may improve treatment outcomes.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
- Metabolism
Background:
- Hepatocellular carcinoma (HCC) exhibits modest response rates to immunotherapy.
- Mechanisms underlying immunotherapy resistance in HCC remain poorly understood.
- The E3 ubiquitin ligase Riplet's role in HCC and immune response is unexplored.
Purpose of the Study:
- To investigate the function of Riplet in hepatocellular carcinoma (HCC).
- To elucidate the mechanisms by which Riplet deficiency impacts T cell function and immunotherapy response in HCC.
- To identify potential therapeutic strategies for overcoming immunotherapy resistance in Riplet-deficient HCC.
Main Methods:
- Analysis of Riplet expression and promoter methylation in HCC.
- Investigating the effect of Riplet loss on CD8 T cell function and fatty acid metabolism.
- Assessing the impact of fatty acid synthase (FASN) inhibition on T cell exhaustion and anti-PD-1 therapy response in HCC models.
Main Results:
- Riplet is universally silenced by promoter hypermethylation in HCC.
- Riplet loss accelerates fatty acid production by impeding FASN ubiquitination, leading to CD8 T cell exhaustion via palmitic acid-mediated STAT3 activation.
- Riplet-deficient HCC demonstrates resistance to anti-PD-1 therapy, which is reversed by FASN inhibition.
Conclusions:
- Riplet deficiency promotes CD8 T cell exhaustion and anti-PD-1 resistance in HCC by altering lipid metabolism.
- Targeting fatty acid metabolism, specifically FASN, offers a promising strategy to overcome immunotherapy resistance in Riplet-deficient HCC.
- Combined therapeutic approaches involving Riplet modulation or FASN inhibition may enhance treatment efficacy for HCC patients.
