Increased Expression Of HVEM In Stroma Of Hepatocellular Carcinoma Is Associated With Large And Poorly Differentiated Tumors

Purpose: Co-signaling molecules, such as B7-1, B7-2, and PD-L1, are among the well-studied mechanisms that may contribute to tumor escape. It has been reported that co-signaling molecules usually demonstrate altered expression levels in some cancers, such as melanoma. Herpesvirus entry mediator (HVEM) is one of the most recently identified cosignaling molecules. The aim of this study was to evaluate the expression profile of HVEM in Hepatocellular Carcinoma (HCC) and its relationship with clinicopathological features of HCC.Experimental Design and Results: HVEM immunohistochemical staining was performed on paraffin sections of HCC and its adjacent noncancerous tissues obtained from HCC resections. HVEM-positive cells were detected in the tumor stroma in 34 of all 57 HCC patients. However, in the fibrous area of adjacent hepatic tissues, HVEM-positive cells were only found in 7 of 57 patients. Double immunofluorescent labeling studies indicated that the majority of HVEM-positive cells were tumor-associated fibroblasts (TAFs), and a small subset of HVEM-positive cells were tumor-associated macrophages (TAMs). Interestingly, the number of HVEM-positive cells in the tumor stroma increased in larger, poorly differentiated tumors.Conclusion: Our results show that HVEM is overexpressed in the tumor stoma of HCC, predominantly in TAFs, and is positively correlated with tumor diameter and differentiation grade. These data reveal an unexpected causal role of HVEM in HCC progression.