Natural-killer-cell–dominant immune landscape and HLA-E–mediated immune evasion in choriocarcinoma
Choriocarcinoma is a rare cancer associated with antecedent pregnancy. Therefore, its development may be influenced by an immune-evasive tumor microenvironment. In this study, we focused on natural killer (NK) cells to elucidate the immune microenvironment of choriocarcinoma. Peripheral blood and intratumoral NK cells were isolated from six samples of four patients with choriocarcinoma. Flow cytometry was used to analyze the NK cell proportion. Immunohistochemistry was performed to assess the expression of NK cell inhibitory ligands using choriocarcinoma tissues from 17 patients. In addition, choriocarcinoma cell lines (JAR, BeWo, and JEG-3) were cocultured with interleukin-2-stimulated NK cells, and loss-of-function analyses of HLA-E were conducted to investigate the impact of NK cells on choriocarcinoma cells. Flow cytometry revealed that NK cells were more abundant in choriocarcinoma tissues than in the peripheral blood. Immunohistochemistry confirmed the expression of NK cell inhibitory ligands, including HLA-E. Moreover, JAR cells were cocultured with NK cells, and viable JAR cells were isolated by flow cytometry. Subsequent mRNA sequencing showed that HLA-E was upregulated, and multiple cytokine-related pathways were activated in the cocultured JAR cells compared with monocultured JAR cells. Functional assays demonstrated that HLA-E knockdown enhanced NK-cell-mediated cytotoxicity, whereas interferon-gamma treatment increased HLA-E expression and promoted tumor cell survival. These findings suggest that NK cells may play an important role in the tumor immune microenvironment of choriocarcinoma through HLA-E expression.