Gastroesophageal adenocarcinoma (GEA) remains one of the deadliest cancers, with limited effective treatment options and a poor prognosis. While immune checkpoint inhibitors have transformed cancer therapy, their benefits in GEA are modest and short-lived, offering only a slight extension in median survival. GEA’s resistance to immunotherapy is poorly understood but likely based on diverse immune evasion mechanisms such as T-cell exclusion and epigenetic reprogramming. With this ASPIRE award, the investigators seek to investigate the role of epigenetics in GEA’s immune responsiveness and resistance to T-cell-mediated killing, hypothesizing that targeting epigenetic pathways can improve outcomes when combined with immune checkpoint inhibitors.
The research leverages patient-derived organoids paired with autologous T-cell cultures to analyze how epigenetic features influence immune resistance. By applying ATAC-seq, ChIP-seq, and RNA-seq analyses to organoids before and after T-cell exposure, the project aims to identify transcriptional and epigenetic programs driving resistance to anti-tumor immunity. Additionally, a comprehensive screen using a library of epigenetic drugs will identify compounds that can restore T-cell sensitivity in resistant GEA organoids. Promising hits will be validated and evaluated for dose-response, on-target effects, and potential for clinical translation.
This approach is one of the first to integrate advanced epigenomic analyses with functional drug screening to uncover novel therapeutic opportunities in GEA. By targeting the epigenetic mechanisms underlying immune resistance, this study aims to enhance the efficacy of immunotherapy and improve outcomes for GEA patients.