Dihydrotestosterone Enhances MICA-Mediated Immune Responses to Epstein–Barr Virus-Associated Gastric Carcinoma.

Simple Summary: Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is a type of stomach cancer linked to EBV infection. This study explores how the male hormone dihydrotestosterone (DHT) affects the immune response against EBVaGC. Using the SNU719 cell line, we treated the cells with DHT and observed an increased expression of the androgen receptor (AR) and the activation of the NF-κB pathway. This led to higher levels of MICA, a protein that interacts with immune cells like natural killer (NK) and T cells, enhancing their ability to kill EBVaGC cells. Importantly, this immune boost occurred without increasing harmful inflammatory signals. Our findings suggest that DHT enhances the immune system's ability to target EBVaGC, providing a potential therapeutic approach by modulating androgen signaling to improve anti-tumor immunity. Background: Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is a subset of gastric cancers linked to EBV infection. While the role of male hormones in cancers such as prostate, breast, and ovarian cancers is well-studied, their impact on EBVaGC remains less understood. This study aims to examine the effect of dihydrotestosterone (DHT) on EBVaGC, particularly focusing on its influence on the immune response. Methods: The study utilized the SNU719 EBVaGC cell line. Cells were treated with DHT to assess androgen receptor (AR) expression and the activation of signaling pathways, including NF-κB. The expression of MHC class I polypeptide-related sequence A (MICA) and its interaction with the NKG2D receptor on NK and T cells was evaluated. Cytotoxicity assays were conducted to determine DHT's effect on NK and T cell-mediated cytotoxicity, and proinflammatory cytokine gene expression was analyzed. Results: DHT significantly increased AR expression in EBVaGC cells and activated the NF-κB pathway, which led to increased transcription of target genes such as MICA and EBNA1. These changes enhanced the interaction with receptors on NK and T cells, thereby boosting their cytotoxicity against EBVaGC cells. Importantly, DHT did not upregulate proinflammatory cytokine genes. Conclusion: DHT enhances the immune response against EBVaGC by upregulating MICA and activating NK and T cells. These findings suggest potential therapeutic strategies targeting androgen signaling to improve anti-tumor immunity in EBVaGC. [ABSTRACT FROM AUTHOR]