Abstract IA019: Cracking the code: Identifying immunogenic targets in high-grade serous ovarian cancer

Abstract Despite advances in immunotherapy, high-grade serous ovarian cancer (OC) remains largely refractory to current treatments. The diversity of antigens expressed in OC has not been fully elucidated, limiting targeted approaches. Using immunopeptidomic profiling of HLA-A02:01+ OC cell lines and metastatic patient samples, we sought to identify a broader range of actionable antigens. Among canonical tumor-associated peptides, we found epitopes from TTLL8, POTEE, and PKMYT1—proteins with minimal expression in normal tissues but elevated in OC. TTLL8, in particular, correlated with poor prognosis and elicited robust CD8+ T cell responses, underscoring its immunogenic potential. In a separate study, we detected 311 cryptic (noncanonical) peptides derived from noncoding genomic regions across five metastatic OC tumor samples. Although representing <1% of total peptides, these cryptic antigens dominated the immunogenic landscape, with nearly 70% inducing autologous CD8+ T cell activation, as measured by 4-1BB and IFN-γ expression. Together, these findings expand the antigenic repertoire of OC and support the development of new immunotherapies targeting both canonical and cryptic tumor antigens. Citation Format: Marion Curtis. Cracking the code: Identifying immunogenic targets in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA019.