AUTHOR=Aguiar Talita , Mashiko Shunya , Asam Kesava , Roy Poulomi , Wang Shikun , Frank Katharina , Dietzel Max , Schahadat Luca G. Z. , Ausmeier Mattea , Hertel Andrea , Duan Zhe Ran Susan , Aouizerat Bradley , Genkinger Jeanine M. , Remotti Helen , Zorn Emmanuel 

TITLE=Development of high-titer class-switched antibody responses to phosphorylated amino acids is prevalent in pancreatic ductal adenocarcinoma

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1501943

DOI=10.3389/fimmu.2025.1501943

ISSN=1664-3224

ABSTRACT=While immunotherapy tends to be ineffective against pancreatic ductal adenocarcinoma (PDAC), this cancer type often elicits B-cell immunity. However, the exact antigens responsible for these spontaneous immune responses are still unclear. This study used a unique high-dimensional ELISA to analyze IgG responses to 93 post-translational modifications and other chemical determinants in PDAC patients at the time of diagnosis and before therapy. Results identified 13 specific targets of serum IgG that distinguished PDAC patients from healthy donors. Phosphorylated-serine, -threonine, and -tyrosine emerged as the primary targets, with most patients showing high-titer IgG, predominantly of the IgG1 and IgG3 subclasses. Moreover, serum reactivity to these phosphorylated residues was higher in patients with metastatic disease, suggesting a relation between B cell immunity and tumor burden. Lastly, immunofluorescence staining and phosphoproteomic analysis provided evidence of the accumulation of phosphorylated amino acids in PDAC cells and identified a series of consensus abnormal phosphosites. Overall, our findings reveal for the first time the development of robust antibody responses targeting phosphorylated residues in PDAC.