High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer

CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs (p = 0.027) but not of Foxp3+ TILs (p = 0.455) and CD20+ TILs (p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis (p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) (p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC (p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245–0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity.

Induction of High Endothelial Venule–like Vessels in Oral and Cutaneous Lichen Planus: A Comparative Study

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease involving the oral mucosa and skin. Both oral LP (OLP) and cutaneous LP (CLP) are histopathologically characterized by dense subepithelial lymphocyte infiltrates; however, the mechanisms underlying lymphocyte recruitment to sites of LP lesions are not fully understood. Here, we assessed the induction of peripheral lymph node addressin (PNAd)-expressing high endothelial venule (HEV)-like vessels in 19 OLP and 17 CLP cases. To do so, we performed immunohistochemical staining for PNAd and CD34, followed by quantitative analysis. We also conducted triple immunohistochemistry for PNAd and either CD3 and CD20 or CD4 and CD8 to identify the lymphocyte subset preferentially recruited via HEV-like vessels. PNAd-expressing HEV-like vessels were induced in and around lymphocyte aggregates in all cases of OLP and in 10 of 17 CLP cases, and these vessels were more frequently observed in OLP relative to CLP. Although the number of T-cells attached per HEV-like vessel exceeded the number of B-cells in both OLP and CLP, the number of CD4+ T-cells attached was greater than the number of CD8+ T-cells only in OLP. These findings combined suggest that PNAd-expressing HEV-like vessels play a more important role in the pathogenesis of OLP compared with CLP.

Role of MAdCAM-1-Expressing High Endothelial Venule-Like Vessels in Colitis Induced in Mice Lacking Sulfotransferases Catalyzing L-Selectin Ligand Biosynthesis

Ulcerative colitis (UC) is a chronic inflammatory disease histologically characterized by diffuse mononuclear cell infiltrates in colonic mucosa. These inflammatory cells are considered to be recruited via high endothelial venule (HEV)-like vessels displaying mucosal addressin cell adhesion molecule 1 (MAdCAM-1), the ligand for α4β7 integrin, and/or peripheral lymph node addressin (PNAd), an L-selectin ligand. 6- O-sulfation of N-acetylglucosamine in the carbohydrate moiety of PNAd is catalyzed exclusively by N-acetylglucosamine-6- O-sulfotransferase 1 (GlcNAc6ST-1) and GlcNAc6ST-2. To determine the role of 6- O-sulfation of N-acetylglucosamine on HEV-like vessels in UC, we used a chronic dextran sulfate sodium–induced colitis model using mice deficient in both GlcNAc6ST-1 and GlcNAc6ST-2. We found that more inflammatory cells, with expression of tumor necrosis factor α, were infiltrated in double knockout mouse colitis compared with that in wild-type mice. Moreover, the number of MAdCAM-1-positive vessels was increased in double knockout mouse colitis, and these vessels were bound by E-selectin•IgM chimeras that bind to unsulfated sialyl Lewis X (sLeX). These findings suggest that interactions between MAdCAM-1 and α4β7 integrin and/or unsulfated sLeX and L-selectin may become a dominant mechanism for inflammatory cell recruitment in the absence of 6-sulfo sLeX and contribute to more severe colitis phenotypes seen in double knockout mice.