High endothelial venules in intracranial germinomas: Implications for lymphocytes infiltration

Abstract

Abstract Purpose Reactive lymphocytes are substantial components of germinoma, which are believed to be related to the favorable prognosis of this intracranial tumor and better response to immunotherapy. However, the mechanisms managing the recruitment of lymphocytes are poorly understood. High endothelial venules (HEVs) are specialized blood vessels that play key roles in lymphocyte trafficking in Lymph nodes. These vessels are associated with lymphocyte infiltration in chronic inflammatory diseases and various malignant tumors, but their distribution and implications in germinoma are unknown. This study aimed to investigate the distribution and implications of HEVs in intracranial germinomas. Methods We investigated the presence and distribution of HEVs in 42 germinomas by immunohistochemical staining of peripheral node addressin (PNAd) and transmission electron microscopic examination. The correlation of the densities of HEVs with the extent of T and B lymphocyte infiltration and several clinicopathological characteristics were also analyzed to determine whether HEVs are responsible for lymphocyte recruitment and their roles in anti‐tumor immunity in germinoma. Results PNAd‐positive HEVs were detected in 31% (13/42) of germinomas, and their presence correlated with abundant infiltrating CD3+ T cells, CD20 + B cells and CD8+ cytotoxic T lymphocytes (p = 0.0410, 0.0023, and 0.0061, respectively). Higher HEVs density was also correlated with several clinicopathological parameters, which are recognized indicators for favorable prognosis in germinomas, including typical tumor location (p = 0.0093), lower tumor cell content (p = 0.0428), and younger age at diagnosis (p = 0.0121). Furthermore, bioinformatics analysis showed HEVs‐associated genes mainly enriched in immune‐related Gene Ontology terms, including innate immune response, inflammatory response, and B cell receptor signaling pathway. The xCell analysis revealed that germinomas with higher HEVs enrichment scores had increased levels of the immune score, microenvironment score, dendritic cells, CD8+ central memory T‐cells, CD4+ memory T‐cells, and B‐cells. Conclusions Our findings indicate that HEVs could contribute to lymphocyte recruitment in germinomas, thus may serve as a predictor of favorable prognosis and better response to immunotherapy in this intracranial tumor.

Keywords

• gene ontology
• germinoma
• high endothelial venules (HEVs)
• peripheral node addressin (PNAd)
• tumor‐infiltrating lymphocytes
• xCell