A Novel Role for the Soluble Isoform of CTLA-4 in Normal, Dysplastic and Neoplastic Oral and Oropharyngeal Epithelia

Abstract

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.

Soluble CTLA-4 raises the threshold for T-cell activation and modulates anti-tumour immunity

“…We show that transforming cancer cells to secrete sCTLA-4 in the TME promotes tumour growth and metastasis by limiting CD8 + T-cell effector activity, demonstrating the functional significance of this less characterised isoform. Some cancer cells have been found to produce sCTLA-4 naturally (15) (36) (37) and we predict that this may lead to blunted T-cell effector activity and immune escape. This is further supported by the finding that cancer cell-intrinsic expression of sCTLA-4 did not provide growth advantage to cancer cells in vitro, or in an immunocompromised host -evidence that largely favours the hypothesis that immune cells, particularly CD8 + T-cells are being held at bay by sCTLA-4.…”