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Updated: Jun 27, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting
James C Ryan1,2, Christina Haight1, Erene C Niemi1
1Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.
Background And Aims:
Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.
Methods:
Participants underwent full HLA class I/KIR typing and long-term HCV follow-up.
Results:
A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC.
Conclusion:
Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.
Insights
Hepatocellular carcinoma (HCC) remains a risk after successful hepatitis C virus (HCV) treatment with direct-acting antivirals (DAA). Weak natural killer (NK) cell immunity, alongside cirrhosis, predicts HCC development post-DAA therapy.
Area of Science:
- Immunology
- Hepatology
- Oncology
Background:
- Second-generation direct-acting antivirals (2G DAA) effectively cure hepatitis C virus (HCV), but hepatocellular carcinoma (HCC) remains a clinical challenge.
- Impaired immune surveillance is a potential factor in HCC development despite viral clearance.
Purpose of the Study:
- To investigate the impact of innate immune profiles and clinical factors on HCC development in HCV patients undergoing antiviral therapy.
- To identify predictors of HCC in patients treated with 2G DAA and those not receiving therapy.
Main Methods:
- A cohort of 353 HCV+ participants underwent human leukocyte antigen (HLA) class I/KIR typing and long-term follow-up.
- Analysis of HCC development in relation to cirrhosis, 2G DAA therapy, and specific HLA/KIR profiles associated with natural killer (NK) cell activity.
Main Results:
- Among 158 patients receiving 2G DAA, HCC developed in 10, with cirrhosis (OR, 10.0) and weak NK cell-mediated immunity (OR, 5.1) as significant predictors.
- In patients not treated with 2G DAA, cirrhosis was the primary predictor of HCC (OR, 30.8), while weak NK cell immunity did not show predictive value.
- Cirrhosis was a common factor, present in 25% at baseline and developing in 12% during follow-up.
Conclusions:
- Cirrhosis is the predominant risk factor for HCC, irrespective of HCV treatment.
- Weak NK cell-mediated immunity may specifically increase the risk of HCC following 2G DAA therapy for HCV, more so than intermediate or strong immunity.
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