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Evaluation of immuno-oncologic biomarkers and β-catenin expression in response of hepatocellular carcinomas to immunotherapy
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  • Published: 20 January 2026

Evaluation of immuno-oncologic biomarkers and β-catenin expression in response of hepatocellular carcinomas to immunotherapy

  • Gaurav Sharma1,
  • Yasmine Baca2,
  • Sanjay Goel3,
  • Anthony F. Shields4,
  • Ajay Prakash5,
  • Benjamin A. Weinberg6,
  • Anwaar Saeed7,
  • Chadi Nabhan2,
  • Matthew Oberley2,
  • Joanne Xiu2,
  • Justin Hwang5,
  • Emmanuel S. Antonarakis5,
  • Vi K. Chiu8 &
  • …
  • Emil Lou5,9 

npj Precision Oncology , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

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  • Cancer
  • Oncology

Abstract

Immune checkpoint inhibitors (ICIs) are utilized to treat hepatocellular carcinomas (HCC) without validated biomarkers. We sought to identify genomic signatures and immune patterns predicting treatment efficacy in 1,306 HCC patients to evaluate for potential predictive biomarkers associated with immunotherapy outcome. Programmed death ligand 1 (PD-L1) expression was high in 6.1% and low in 11.6%; deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) was detected in only 0.2%, and high tumor mutational burden (TMB-H) in 5.1% of the patients. Immuno-oncologic (IO) markers (CD80, HAVCR2, PDCD1, IFNG, CTLA4, IDO1, CD86, LAG3, PDCD1LG2) correlated with PD-L1 expression (q < 0.05). Infiltration of B cells, M1 macrophages, CD8 + T cells, and Tregs also increased with PD-L1 expression (q < 0.05). CTNNB1 mutations occurred more in PD-L1 negative (35%) than in PD-L1 high (21%) patients (p = 0.03). PD-L1 expression did not affect ICI treatment duration, but CTNNB1-high levels were associated with a shorter duration of treatment in PD-L1 negative tumors (p = 0.04). However, in IO non-exposed tumors, CTNNB1-high expression was associated with improved overall survival (HR = 0.97, 95% CI 0.96-0.98, p < 0.00001). In conclusion, our analysis indicates that expression of PD-L1, CTNNB1, and other molecular markers most associated with IO response in other gastrointestinal malignancies are not directly indicative of such responses in HCC.

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Data availability

Caris Life Sciences owns the deidentified sequencing data, which cannot be publicly shared due to the data usage agreement in place. These data will be made available to researchers for replication and verification purposes through our letter of intent process, which is generally fulfilled within 6 months. For more information on how to access this data, please contact Dr. Joanne Xiu at [jxiu@carisls.com](mailto:jxiu@carisls.com).

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Acknowledgements

EL thanks the following groups for donations in support of cancer research: Friends and family of Gayle Huntington, the Mu Sigma Chapter of the Phi Gamma Delta Fraternity, University of Minnesota (FIJI), the Litman Family Fund for Cancer Research, Dick and Lynnae Koats, Ms. Patricia Johnson, and Love Like Laurie Legacy. This study has no funding support. However, ESA is partially supported by NCI Cancer Center Support Grant P30 CA077598 and DOD Grant W81XWH-22-2-0025. EL reports research grants from the American Cancer Society (RSG-22-022-01-CDP) 2022-2026, and Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022.

Author information

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

    Gaurav Sharma

  2. CARIS Life Sciences, Phoenix, AZ, USA

    Yasmine Baca, Chadi Nabhan, Matthew Oberley & Joanne Xiu

  3. Rutgers Cancer Institute, New Brunswick, NJ, USA

    Sanjay Goel

  4. Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Anthony F. Shields

  5. Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Ajay Prakash, Justin Hwang, Emmanuel S. Antonarakis & Emil Lou

  6. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    Benjamin A. Weinberg

  7. University of Pittsburgh, Pittsburgh, PA, USA

    Anwaar Saeed

  8. The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, Los Angeles, CA, USA

    Vi K. Chiu

  9. Graduate Faculty, Integrative Biology and Physiology Department, University of Minnesota, Minneapolis, MN, USA

    Emil Lou

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Contributions

E.L. conceived the study design. G.S., Y.B., and E.L. performed initial analysis of data. G.S. and E.L. drafted the manuscript. J.H., E.S.A., A.S., S.G., A.P., B.A.W., A.S., and V.K.C. reviewed and edited the study and made major revisions. All authors read the manuscript and provided critical analysis and edits. All authors read and approved the final version for submission.

Corresponding author

Correspondence to Emil Lou.

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Competing interests

EL disclosed the following financial relationships from the past two years: equipment for laboratory-based research 2018-present, Novocure, Ltd; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2+ gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to lab); compensation for scientific review of proposed printed content; Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Bioscience, Inc., the National Cancer Institute, and the University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). ESA has served as a paid consultant/advisor for Sanofi, Dendreon, Janssen Biotech, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer, and has received honoraria from Sanofi, Dendreon, Janssen Biotech, Astellas Pharma, Merck, AstraZeneca, and Clovis Oncology; has received research funding from Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology, and Constellation Pharmaceuticals, a well as travel accommodations from Sanofi, and Dendreon; He is a co-inventor of a biomarker technology licensed to Qiagen. AS reports a leadership role with Autem therapeutics, Exelixis, KAHR medical and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. YB, CN, and JX are employees of Caris Life Sciences. The authors declare no other financial or non-financial interests.

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Sharma, G., Baca, Y., Goel, S. et al. Evaluation of immuno-oncologic biomarkers and β-catenin expression in response of hepatocellular carcinomas to immunotherapy. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01275-7

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  • Received: 05 June 2025

  • Accepted: 07 January 2026

  • Published: 20 January 2026

  • DOI: https://doi.org/10.1038/s41698-026-01275-7

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