Differential Regulation of Soluble and Membrane 4-1BB and OX-40 Within the Peripheral Compartment of Cervical Cancer

Abstract

Background: Members of the tumor necrosis factor receptor superfamily (TNFRSF), including 4-1BB (CD137) and OX-40 (CD134), play central roles in regulating cytotoxic lymphocyte activation and anti-tumor immunity. In addition to their membrane-bound forms, soluble receptor isoforms may modulate signaling by influencing ligand availability and receptor engagement. However, the peripheral regulation of soluble and membrane 4-1BB and OX-40 in cervical cancer remains incompletely defined. Methods: Plasma concentrations of soluble 4-1BB (s4-1BB) and soluble OX-40 (sOX-40) were quantified by ELISA in 20 treatment-naïve cervical cancer (CC) patients and 20 healthy controls (HCs). Membrane expression (m4-1BB and mOX-40) on circulating T cells and NK cells was evaluated by flow cytometry. Correlation and stage-stratified analyses were performed. Results: Plasma levels of s4-1BB and sOX-40 were significantly elevated in CC patients compared with HCs. Membrane 4-1BB expression was increased on both T cells and NK cells, while OX-40 expression was selectively elevated in NK cells, with no difference observed in T cells. A moderate positive correlation was identified between s4-1BB and T-cell membrane 4-1BB expression. Notably, membrane 4-1BB expression decreased in advanced-stage disease, whereas soluble concentrations remained unchanged. Conclusions: These findings demonstrate differential regulation of soluble and membrane 4-1BB and OX-40 in the peripheral compartment in cervical cancer, highlighting distinct regulatory layers within the TNFRSF axis.