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Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes

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Abstract

Background and objective

Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes.

Patients and methods

The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry.

Results

Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS.

Conclusion

Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.

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Abbreviations

APC:

Allophycocyanin

CCL5-CCR5:

Chemokine ligand 5-chemokine receptor 5

DAA:

Direct-acting antiviral drugs

FITC:

Fluoroisothiocyanate

FLR:

Future liver remnant

HCC:

Hepatocellular carcinoma

OS:

Overall survival

PBMCs:

Peripheral blood mononuclear cells

PBS:

Phosphate buffer saline

PD-1:

Programmed cell death protein-1

PE:

Phycoerythrin

Per-CP:

Peridinium-chlorophyll-protein

PS:

Performance status

RFA:

Radiofrequency ablation

TACE:

Trans-arterial chemo-embolization

Tim-3:

T-cell immunoglobulin and mucin-domain containing-3

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Authors and Affiliations

  1. Clinical Pathology Department, South Egypt Cancer Institute, Assiut, Egypt

    Asmaa M. Zahran

  2. Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt

    Helal F. Hetta & Omnia El-Badawy

  3. Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Helal F. Hetta

  4. Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, Egypt

    Amal Rayan

  5. Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt

    Abeer Sharaf Eldin & Elham Ahmed Hassan

  6. Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt

    Hussein Fakhry

  7. General Surgery Department, Faculty of Medicine, Assiut University, Assiut, Egypt

    Ahmed Soliman

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  1. Asmaa M. Zahran
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  2. Helal F. Hetta
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  3. Amal Rayan
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  4. Abeer Sharaf Eldin
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  7. Ahmed Soliman
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  8. Omnia El-Badawy
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Contributions

AMZ, HFH, AR and OE-B conceived and designed the experiments. AR, ASE, EAH, HF and AS recruited patients, carried out the clinical investigations and collected patients’ clinical data. AMZ performed the experiments. AMZ, HFH and OE-B shared in the analysis of the flow cytometry data. OE-B. performed the statistical analysis. OE-B and AMZ accomplished the interpretation of results and wrote the initial draft. All authors participated in critical review and revision of the final manuscript, and HFH managed the submission of the manuscript.

Corresponding author

Correspondence to Helal F. Hetta.

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The research was done according to the ethical guidelines of the Declaration of Helsinki 1975 and was accepted by the local ethics committee of the Faculty of Medicine, Assiut University, Assiut, Egypt (IRB no: 17300300).

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Written informed consent was obtained from all participants before inclusion in the study. Participants consented for the use of their specimens and data for research and publication.

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Zahran, A.M., Hetta, H.F., Rayan, A. et al. Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes. Cancer Immunol Immunother 69, 1253–1263 (2020). https://doi.org/10.1007/s00262-019-02465-y

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