P08.16 Enhancing the immunogenicity of esophagogastric adenocarcinoma by restoring antigen presentation and tumor-associated antigens using epigenetic drugs

Background Immune checkpoint inhibitors (ICIs) have expanded treatment options for esophagogastric adenocarcinoma (EGA), but primary and secondary resistance limit durable benefit to a subset of patients. Defective antigen processing and presentation is a key mechanism of immune escape and remains poorly understood in EGA. Genes involved in the antigen processing and presentation machinery (APM) are regulated by epigenetic and inflammatory pathways, which are likely susceptible to therapeutic modulation.Methods Genomic and transcriptomic alterations in APM pathways were analyzed in 43 EGA tumors and validated in an independent TCGA cohort (n = 419). Protein expression of 10 key APM components was assessed by immunohistochemistry (n = 123). EGA cell lines were treated with epigenetic and pro-inflammatory agents, and effects on tumor-associated antigen (TAA) expression, APM component expression, apoptosis, and the immunogenic peptide repertoire were evaluated by flow cytometry and immunopeptidomics. T-cell abundance (immune score) and tertiary lymphoid structures (TLS) in primary tumors were assessed as surrogates of immunogenicity.Results Although antigen processing and presentation pathways were globally upregulated in tumor tissue compared with patient-matched normal tissue, marked inter-patient heterogeneity and tumor-specific APM dysregulation were observed. APM expression correlated with DNA methylation and interferon-γ signatures, suggesting epigenetic and inflammatory regulation of the APM. Pharmacological modulation with epigenetic and pro-inflammatory drugs restored APM and TAA expression and increased the abundance of potentially immunogenic peptides. Dysregulation of APM-associated molecules was associated with reduced immune scores and TLS abundance.Conclusion APM dysfunction represents a frequent and therapeutically druggable mechanism of immune escape in EGA. Epigenetic and pro-inflammatory strategies can restore antigen presentation, enhance tumor immunogenicity, and support combination approaches with immunotherapy to overcome resistance. M.v.B-B: received honoraria for advisory board participation and invited talks from BMS, and financial support for research projects from Astellas, Roche, and MSD. H.A.S: received financial support for research projects from AstraZeneca, unrelated to the content of this project. All other authors declare no conflicts of interest relevant to the content of this project.