CTLA-4 and PD-1 Ligand Gene Expression in Epithelial Thyroid Cancers.

Chiara Tuccilli,Giovanni Carbotta,Massimo Vergine,Enke Baldini,Daniele Pironi,Stefano Arcieri,Salvatore Ulisse,Francesco Tartaglia,Caterina Mian,Massimo Monti,Susi Barollo,Andrea Palmieri,Poupak Fallahi,Salvatore Sorrenti,Alessandro Antonelli,Antonio Catania

doi:10.1155/2018/1742951

Abstract

The dysregulation of PD-1 ligands (PD-L1 and PD-L2) and CTLA-4 ligands (CD80 and CD86) represents a tumor strategy to escape the immune surveillance. Here, the expression of PD-L1, PD-L2, CD80, and CD86 was evaluated at the mRNA level in 94 patients affected by papillary thyroid carcinoma (PTC) and 11 patients affected by anaplastic thyroid carcinoma (ATC). Variations in the mRNAs in PTC patients were then correlated with clinicopathological features. The expression of all genes was deregulated in PTC and ATC tissues compared to normal tissues. In particular, the downregulation of CD80 was observed above all in ATC. In addition, the increased expression of CD80 associated with longer disease-free survival in PTC. Higher expression of PD-L1 associated with the classical histological variant and with the presence of BRAFV600E mutation in PTC. The increased PD-L2 expression correlated with BRAFV600E mutation and lymph node metastasis, while its lower expression correlated with the follicular PTC variant. The latter was also associated with the CD80 downregulation, which was also related to the absence of lymph node metastasis. In conclusion, we documented the overall dysregulation of PD-1 and CTLA-4 ligands in PTC and ATC tissues and a possible prognostic value for CD80 gene expression in PTC.

Highlights

Based on experimental mouse models and clinical studies, tumor infiltration by cells of the innate and adaptive arms of the immune system is thought to reflect a physiological attempt to eradicate incipient tumor, late-stage cancers, and micrometastases [1,2,3,4,5,6]
Considering the importance of the identification of new prognostic molecular markers for aggressive differentiated carcinomas (DTC), the necessity of new therapeutic approaches for the most aggressive thyroid cancers [26,27,28,29,30,31], and the promising results obtained by inhibitors of immune checkpoint molecules in clinical trials [48], the aim of this work was to investigate the expression, at the mRNA level, of CTLA-4 and PD-1 ligands in a case study consisting of 94 papillary thyroid carcinoma (PTC) and 11 anaplastic thyroid carcinoma (ATC) tissues
The analysis of the mRNA levels of CTLA-4 and PD-1 ligands in PTC samples, compared to normal matched tissues, revealed that the expression of all transcripts was dysregulated in the majority of cases (Figure 1)

Summary

Introduction

Based on experimental mouse models and clinical studies, tumor infiltration by cells of the innate and adaptive arms of the immune system is thought to reflect a physiological attempt to eradicate incipient tumor, late-stage cancers, and micrometastases [1,2,3,4,5,6]. Malignant cells may express ligands for the immune checkpoint CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death 1), present on the surface of activated T lymphocytes, inhibiting their functions [14,15,16,17,18,19]. Effective activation of T cells requires the engagement of two separate T cell receptors. The antigen-specific T cell receptor (TCR) binds foreign antigenic peptide-MHC

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