樋田 泰浩

OBJECTIVES: Surgery, chemotherapy, and radiation therapy are currently used for the treatment of malignant tumors, and immunotherapy has recently been established as the fourth method for treating cancer. Therefore, cancer cells and their surrounding microenvironments have been the focus of attention. High endothelial venules (HEVs) that mediate lymphocyte extravasation into lymphoid organs have been reported in cancerous tissues. However, the role of HEVs remains controversial. In this study, the clinical significance of HEVs in patients with oral squamous cell carcinoma (OSCC) was examined. METHODS: Eighty-three patients with OSCC of the tongue who had surgery as initial treatment were included. HEVs and lymphocytes were immunohistochemically stained, and their numbers and localization were evaluated. RESULTS: The prognosis significantly improved in patients with a high number of HEVs. Additionally, localization of HEVs to the tumor margins was associated with a good prognosis. Patients with localized infiltration of CD8-positive cells at the tumor margin had a significantly better prognosis, although no correlation was observed between the number of CD8-positive cells around the HEVs and the prognosis. Cox proportional hazards model revealed that TNM Stage, localization of HEVs, and localization of CD8-positive cells are prognostic factors affecting disease-free survival in patients with OSCC. CONCLUSIONS: The localization of HEVs and CD8-positive cells affect the prognosis of patients with OSCC and they are beneficial prognostic factors.

OBJECTIVE: The density of tumor-associated high endothelial venule (TA-HEV) correlates with a favorable prognosis in various tumors, including oral squamous cell carcinoma (OSCC). Despite the association of TA-HEVs with a better prognosis, their changes during tumor progression remain unclear. Therefore, this study aimed to examine these alterations in a mouse OSCC model. METHODS: Mice were treated with water containing 4NQO to establish a mouse OSCC model. Immunohistochemical analyses were performed using CD31 and MECA 79 antibodies to evaluate TA-HEV alterations during tumor progression. RESULTS: Tongue samples were histologically classified into untreated, normal, dysplasia, and carcinoma groups. During the dysplastic stage, the number of blood vessels increased, and pericyte coverage was reduced as the carcinoma developed. Moreover, HEVs were more abundant in the dysplasia and carcinoma groups, with an increased number of HEVs infiltrated with CD8+ T cells as the lesion progressed. The location and morphology of the HEVs changed during the transition from normal tissue to carcinoma, with the distribution of the TA-HEVs associated with the tumor growth patterns. Specifically, TA-HEVs were frequently found within the tumor in endophytic carcinomas, and at the tumor margins in exophytic carcinomas. Margin TA-HEVs correlated with a higher number of T cells than HEVs within the tumors. CONCLUSION: OSCC-associated HEVs increase in density with tumor progression, and margin TA-HEVs suggests a better anti-tumor prognosis compared with intra-TA-HEVs.

Aging is a risk factor for severe COVID-19, characterized by vascular endothelial dysfunction. Although possible susceptibility of vascular endothelial cells (ECs) to SARS-CoV-2 infection has been suggested, the details of entry into cells have not been clarified. Previously, we reported that in an aged mouse model of severe COVID-19, ECs show a massive viral uptake and inflammatory response. Here, we focused on the endocytic capacity of senescent ECs. We found that the senescent ECs showed high endocytic capacity and SARS-CoV-2 virus uptake. This triggers an nuclear factor-kappa B (NF-κB) pathway-mediated inflammatory response. Further, Basigin enhanced endocytosis in the senescent ECs by activating the intracellular vascular endothelial growth factor signaling. Thus, EC senescence is associated with enhanced SARS-CoV-2 endocytosis and subsequent vascular endothelial dysfunction. This could prove a potential target for treating severe COVID-19 in older adults.

Severe COVID-19 shows a high incidence of pulmonary thrombosis. However, the molecular mechanism underlying this phenomenon remains unclear. We have performed RNA sequencing of isolated endothelial cells (ECs) from infected mid-aged and young mice. Compared to young mice, Integrinβ3 (ITGB3) expression levels were higher in ECs of mid-aged mice which showed thrombosis in lungs. SARS-CoV-2 exposure increased the number of adhered platelets on the EC monolayer in vitro. Knockdown of ITGB3 in ECs decreased platelet adhesion to them. Among the molecules known as SARS-CoV-2 receptors, Kringle-containing transmembrane protein 1 contributed to ITGB3 upregulation in ECs by SARS-CoV-2. Histological analysis showed that ITGB3-positive blood vessels were frequently detected not only in infected-mid-aged mouse lungs but also in COVID-19-affected human autopsy lungs. This study suggests that the induction of ITGB3 expression in ECs is one of the mechanisms of thrombosis in severe COVID-19 pneumonia.