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Updated: Dec 23, 2025
Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma
Published on: April 25, 2025
Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma
Won Jin Ho1,2, Ludmila Danilova2,3, Su Jin Lim1,2
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Background And Aims:
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear.
Methods:
We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)).
Results:
Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=-1.4%, 95% CI: -13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC.
Conclusion:
There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.
Insights
Viral status does not impact the effectiveness of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway inhibitors in hepatocellular carcinoma (HCC). Therefore, viral etiology should not influence patient selection for these immunotherapies.
Area of Science:
- Oncology
- Immunology
- Hepatology
Background:
- Hepatocellular carcinoma (HCC) often arises in patients with chronic viral hepatitis.
- Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway show efficacy in HCC, but response rates vary.
- The influence of viral status on the tumor immune microenvironment and ICI response in HCC is not well understood.
Purpose of the Study:
- To investigate the impact of viral etiology on the tumor immune microenvironment in HCC.
- To determine if viral status affects clinical response rates to PD-1/PD-L1 inhibitors in HCC patients.
- To identify potential biomarkers for improving ICI efficacy in HCC.
Main Methods:
- A meta-analysis was performed to compare objective response rates (ORR) of PD-1/PD-L1 inhibitors in virally-infected versus uninfected HCC patients.
- The tumor immune microenvironment was analyzed using The Cancer Genome Atlas (TCGA) data.
- Peripheral blood immune responses were assessed using mass cytometry (CyTOF) in an independent patient cohort.
Main Results:
- Meta-analysis revealed no significant difference in ORR between virally-infected and uninfected HCC patients treated with PD-1/PD-L1 inhibitors.
- Viral etiology did not correlate with key features of the tumor immune microenvironment or tumor mutational burden.
- Analysis of T cell and B cell repertoires, as well as peripheral blood immune markers, showed no impact of viral status.
Conclusions:
- Viral etiology does not significantly alter the tumor immune microenvironment in HCC.
- Patient viral status should not be a criterion for selecting individuals for PD-1/PD-L1 inhibitor therapy in HCC.
- Further research is needed to identify reliable biomarkers for ICI response in HCC.
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