Reduced Activity of Soluble Fibroblast Activation Protein (sFAP) Represents a Biomarker of Aggressive Disease in Lymphoid Malignancies

Fibroblast activation protein (FAP), a transmembrane serine protease expressed primarily in pathological conditions, plays a pivotal role in tumor progression. Despite extensive studies on FAP in solid tumors, its role in hematologic cancers, particularly lymphoid malignancies, remains underexplored. This study aimed to investigate the level and activity of soluble FAP (sFAP) in pre-therapeutic serum samples from 120 lymphoma patients. We measured sFAP serum levels using time-resolved immunofluorometric assay and sFAP activity with Förster resonance energy transfer assay. In addition, immunohistochemistry was used to analyze intratumoral FAP expression in tissue biopsies from a subset of B-cell lymphoma patients (<i>n</i> = 34). Notably, the results revealed significantly reduced circulating sFAP levels (<i>p</i> = 0.002) and activity (<i>p</i> < 0.001) in aggressive disease subtypes compared with indolent subtypes and healthy individuals. At the time of diagnosis, low sFAP activity correlated with inferior overall survival (both <i>p</i> < 0.001) in patients with the aggressive entities, suggesting altered FAP functionality in these tumors. Interestingly, measuring intratumoral FAP levels revealed an inverse pattern, with diffuse large B-cell lymphoma showing higher tissue FAP localization compared with follicular lymphoma (<i>p</i> < 0.001). These findings provide new insights into the biological and clinical significance of FAP in lymphoid malignancies, particularly highlighting the importance of sFAP activity as a potential prognostic marker in aggressive lymphoid malignancies.