Clinical Impact of Herpesvirus Entry Mediator (HVEM) in Malignant Liver Tumors

Abstract

Background: Herpes virus entry mediator (HVEM), also known as tumor necrosis factor receptor (TNFR) superfamily 14, regulates a variety of physiological and pathological responses in both innate and acquired immunity. Recently, HVEM is also suggested to be a critical regulator in tumor immunity. This study aimed to clarify clinical importance of HVEM in human hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Methods: This study examined 150 patients with HCC and 104 patients with CRLM who underwent curative liver resection at Nara Medical University between 2000 and 2014. Immunohistochemical staining was performed using antibodies against HVEM, CD4, CD8, and CD45RO. Results: High HVEM expression was observed in 66 of 150 patients (44.0%) with HCC, and 49 of 104 patients (47.1%) with CRLM. Expression of HVEM was not associated tumor size, number of tumors, or histologic differentiation. The high-HVEM group exhibited significantly worse overall survival (OS) than the low-HVEM group (HCC: P=0.002, CRLM: P = 0.002). Multivariate analysis showed that independent poor prognostic factors of OS for HCC were high HVEM expression in HCC and tumor size >5 cm, while in CRLM, high HVEM expression in CRLM, age of 70 years or older, and having five or more tumors were prognostic factors of OS. HVEM status was inversely correlated with tumor-infiltrating CD8+ and CD45RO+ lymphocytes in both HCC and CRLM. Conclusions: Tumour-expressing HVEM might play a critical role in human HCC and CRLM, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC and CRLM.