Overexpression of HHLA2 is Markedly Associated with the Poor Prognosis in Medullary Thyroid Carcinoma

Abstract Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a newly identified immune checkpoint molecule that was aberrantly expressed in many malignant tumors. However, its expression in medullary thyroid carcinoma (MTC) is still unclear. This study aimed to investigate the HHLA2 expression in MTC tissues and to evaluate the relationships between its expression and clinicopathologic together with prognostic relevance. Using 51 surgical specimens obtained from MTC patients, the expression levels of the HHLA2 protein in MTC tumor tissues and adjacent noncancerous tissues were measured by immunohistochemistry, and its correlations with clinicopathologic and prognostic features were analyzed. Status of CD8+ tumor-infiltrating lymphocytes (TILs) was also investigated. The results showed that HHLA2 was only detected in tumor tissues, and that 31.4% of the MTC patients had high expression of HHLA2. High HHLA2 expression was significantly associated with lymph node metastasis and advanced AJCC stages (P=0.005). There existed an inverse trend between HHLA2 expression and CD8+ TILs infiltration in MTC tumor samples (P=0.042). The log-rank test showed a shorter disease-free survival in patients with high HHLA2 expression (P=0.002). The disease-free survival rates were also significantly low in cases of MTC with lymph node metastasis, AJCC stages III-IV and multifocality. Multivariate Cox analysis confirmed that HHLA2 acted as an independent predictive factor in the disease-free survival of MTC patients (HR=4.138, 95%CI: 1.027-16.667, P=0.046). Taken together, HHLA2 is highly expressed in MTC patients, and is a poor prognostic biomarker of disease-free survival of MTC patients.