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Cited by 132Cancer Immunotherapy and BiomarkersHepatocellular Carcinoma Treatment and PrognosisHepatitis B Virus Studies

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

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Shrestha, Ritu, Prithviraj, Prashanth, Anaka, Matthew, Bridle, Kim R., Crawford, Darrell H. G., Dhungel, Bijay, Steel, Jason C., Jayachandran, Aparna·2018·Frontiers in Oncology
DOI 10.3389/fonc.2018.00269PMC PMC6053505
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Abstract

The global burden of Hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules PD-L1, PD-1 and CTLA-4 and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73 and VISTA predicted low recurrence free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73 and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high TMB predicted worse patient outcomes than those with low TMB.

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  • B7H4, PDL1, and TIM3 are all associated with mortality in HCC.

    “which are all associated with mortality in HCC (53)”

    From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [53]

    The Abstract and Discussion associate B7-H4 and TIM-3 with worse prognosis or overall survival in HCC. The Results section on coordinated immune-regulator expression reports that PD-L1 expression alone did not show poor survival; worse survival was associated with PD-L1 in combination with other markers. The claim omits that qualification for PD-L1. Page numbers are not available in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • B7H4 and TIM3 mRNA showed hypoxia-induced expression in vehicle-treated but not in 32-134D-treated Hepa1-6 cells (P < 0.05).

    “B7H4 and TIM3 mRNA, which are encoded by the Vtcn1 and Havcr2 genes, respectively, and like PDL1, encode immune checkpoint receptors that are HIF regulated (51, 52) and associated with patient mortality in HCC (53), showed hypoxia-induced expression in vehicle-treated but not in 32-134D–treated cells (P < 0.05; Figure 3B).”

    From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [53]

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Authors
Shrestha, R., Prithviraj, P., Anaka, M., Bridle, K. R., Crawford, D. H. G., Dhungel, B., Steel, J. C., & Jayachandran, A.
Affiliations
  • The University of Queensland (AU)
  • University of Alberta (CA)
Corresponding author
Jayachandran, Aparna
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2018-07-13
Volume
8
Pages
269-269
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2018.00269
PMC
PMC6053505
OpenAlex
W2884098295
Cited by
132
References
5
Citations by year
2026: 3 · 2025: 4 · 2024: 11 · 2023: 16 · 2022: 33 · 2021: 34 · 2020: 19 · 2019: 10 · 2018: 2
FWCI
6.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Acquire (CQUniversity) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
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, predictive biomarkers, immune checkpoint inhibitors, PD-L1, PD-1, CTLA-4, B7-H4, PD-L2, TIM-3, VISTA, CD73, epithelial-mesenchymal transition, tumor mutational burden, prognosis, recurrence, overall survival, immune evasion

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