A novel role for the soluble isoform of CTLA-4 in normal, dysplastic and neoplastic oral and oropharyngeal epithelia

Prarthna Clare, Farah Muthanna Al-Fatyan, Badri Risheh, Kristine Nellany, Frank Ward, Rasha Abu Eid* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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Background: Head and neck cancer (HNC) has a high mortality rate, with late diagnosis remaining the most important factor affecting patient survival. Therefore, it is imperative to identify markers that aid in early detection and prediction of disease progression. HNCs evade the immune system by different mechanisms, including immune checkpoints. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is an immune checkpoint receptor that downregulates anti-tumour immune responses, with evidence of involvement in HNC. The less studied, alternatively spliced, soluble isoform (sCTLA-4) also plays an immunosuppressive role that contributes to immune escape. We quantified sCTLA-4 in normal, potentially malignant, and malignant oral and oropharyngeal tissues to elucidate any role in tumourigenesis and identify its potential as a biomarker for diagnosis and patient stratification. Methods: Normal, low- and high-grade epithelial dysplasia, and squamous cell carcinoma oral and oropharyngeal biopsies were selectively stained for sCTLA-4 and quantified using the image analysis software QuPath. Results: Distinct sCTLA-4 staining patterns were observed, in which normal epithelial sCTLA-4 expression correlated with keratinocyte differentiation, while disrupted expression, both in intensity and localisation, was observed in dysplastic and neoplastic tissues. Conclusions: Our data indicate an additional, previously unknown role for sCTLA-4 in epithelial cell differentiation and proliferation. Furthermore, our findings suggest the potential of sCTLA-4 as a biomarker for predicting disease progression and patient stratification for targeted HNC therapies.
Original languageEnglish
Article number1696
Number of pages16
Issue number6
Early online date10 Mar 2023
Publication statusPublished - 10 Mar 2023

Bibliographical note

Acknowledgments: The authors would like to acknowledge the NHS Grampian Biorepository for their help in acquiring samples, especially Andrea Chapman for confirming the diagnosis of the samples. Microscopy was performed in the Microscopy and Histology Core Facility at the University of Aberdeen. We thank the following for their work during their summer projects: Rory Maciver (INSPIRE National Scholarship, Academy of Medical Sciences through the University of Aberdeen), Ramisha Basharat (summer scholarship by the Development Trust of the University of Aberdeen through funds from CRANES, Scotland), Sara Lucila Lorenzo Guerra (ERASMUS+), and Khaled Shawki (currently at Horus University, Egypt).

Funding: This work was supported by funding from Friends of Anchor (RS 17 007), TENOVUS Scotland (G17.11), and the NHS Endowment Grant (17/042 and 18/24). P.C., F.A.-F. and B.R. were funded by the University of Aberdeen doctoral Elphinstone Scholarship.


  • CTLA-4
  • sCTLA-4
  • head and neck cancer
  • oral epithelial dysplasia
  • oral potentially malignant disorder
  • immune checkpoints
  • image analysis
  • oral potentially malignant disorders


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