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Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma
Open accessAbstract
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.
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Ho et al. found no significant differences in TME immune cell infiltration subtypes or immune checkpoint molecule expression levels between HCC patients with and without HBV/HCV infections treated with PD-1/PD-L1 inhibitors.
“Ho et al. compared the clinical benefits of PD-1/PD-L1 inhibitors in HCC patients with and without HBV/HCV infections, finding no significant differences in TME immune cell infiltration subtypes or immune checkpoint molecule expression levels108.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [108]
The Results section, “Tumor immune microenvironment in HCV, HBV, and uninfected HCC” (page unavailable), reports no significant association of viral etiology with markers of several infiltrating immune-cell types or with tumor immune-checkpoint expression. But those TME findings came from TCGA tumor data, not from the patients treated with PD-1/PD-L1 inhibitors; the paper analyzed treatment responses separately. The claim incorrectly presents the TME comparison as a finding in treated patients. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe discrepancy in predictive role of viral status may be related to the balance of inflammation and immune recognition mechanisms within the TME.
“This discrepancy may be related to the balance of inflammation and immune recognition mechanisms within the TME108,109.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [108]
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Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors
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“This discrepancy may be related to the balance of in fl ammation and immune recognitionmechanismswithintheTME 108,109 .”
Metadata
- Authors
- Ho, W. J., Danilova, L., Lim, S. J., Verma, R., Xavier, S., Leatherman, J. M., Sztein, M. B., Fertig, E. J., Wang, H., Jaffee, E., & Yarchoan, M.
- Affiliations
- Johns Hopkins University (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Yarchoan, Mark
- ORCID
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2020-04
- Volume
- 8
- Issue
- 1
- Pages
- e000394
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC7204805
- OpenAlex
- W3017091658
- Cited by
- 66
- References
- 2
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 17 · 2022: 8 · 2021: 12 · 2020: 3
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Cancer Institute (P30 CA006973, P50 CA062924, T32CA00971-38, U01 CA212007)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- hepatocellular carcinoma, immune checkpoint inhibitors, PD-1/PD-L1 pathway, viral infection, hepatitis B, hepatitis C, tumor immune microenvironment, objective response rate, tumor mutational burden, immune-related biomarkers, immunotherapy selection, mass cytometry
- MeSH terms
- Clinical Decision-Making, Immune Checkpoint Inhibitors, Antigens, Viral, Hepatitis B virus, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Retrospective Studies, T-Lymphocytes, Hepacivirus, Lymphocytes, Tumor-Infiltrating, Patient Selection, Hepatitis B, Chronic, Hepatitis C, Chronic, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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