Abstract 6145: Serological responses to phosphorylated adducts in pancreatic ductal adenocarcinoma

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by late-stage diagnosis and poor survival rates. Identifying biomarkers that can aid in early detection and disease characterization is critical. This study leverages a novel ELISA platform to explore IgG reactivity to chemical adducts in the plasma of PDAC patients compared to healthy donors (HD). Materials and Methods: Plasma samples from 39 PDAC patients and 40 age- and sex-matched HD were analyzed for IgG reactivity to 93 adducts, including phosphorylated amino acids, advanced glycation end products, and coenzymes. Reactivity to phosphoryl-Thr, -Ser, and -Tyr were further validated and characterized using IgG1-4-specific secondary antibodies. Paired tumor and non-tumoral tissues from a subset of cases underwent immunofluorescence and phosphoproteomic analyses to identify phosphorylation changes. Results: Serum IgG reactivity to phosphorylated threonine, serine, and tyrosine was significantly higher in patients with pancreatic ductal adenocarcinoma (PDAC) than in healthy donors (HD). A Boruta-based random forest classifier identified these phosphorylated adducts as the most significant target adducts discriminating between the two groups. High-titer IgG responses to these phosphorylated adducts—predominantly IgG1 and IgG3—were observed for PDAC patients. Moreover, patients with metastatic disease exhibited greater IgG reactivity to phosphorylated adducts than those without metastasis. Immunofluorescence analysis demonstrated the accumulation of phosphorylated adducts in PDAC cells, suggesting that their abundance in the tumor triggered the specific antibody response. Additionally, phosphoproteomics revealed dysregulated phosphorylation pathways in PDAC, with 124 proteins showing significantly higher phosphorylation levels in tumor tissue compared to non-tumoral tissue. Gene ontology analysis linked these proteins to processes involving chromatin organization, transcription regulation, and histone acetylation. Essential molecular functions of these aberrantly expressed proteins included chromatin and RNA binding, evoking altered gene expression. Conclusion: Serum IgG responses to phosphoryl adducts represent a robust biomarker for PDAC detection and may reflect disease progression. These findings highlight the potential of anti-adduct IgG profiles as tools for early cancer detection and therapeutic monitoring. Citation Format: Talita Aguiar, Shunya Mashiko, Kesava Asam, Poulomi Roy, Shikun Wang, Katharina Frank, Max Dietzel, Luca G. Z. Schahadat, Mattea Ausmeier, Andrea Hertel, Zhe Ran S Susan Duan, Bradley Aouizerat, Jeanine M. Genkinger, Helen Remotti, Emmanuel Zorn. Serological responses to phosphorylated adducts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6145.