Membrane (m) CD58 is a co-stimulatory ligand that binds to CD2, and the CD2-(m) CD58 axis participates in lymphocyte activation. In addition to mCD58, a soluble form of CD58 (sCD58) has been reported in human serum, urine, and in vitro cell culture supernatants. The role of sCD58 in the tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC) is currently unknown. The expression and prognostic role of CD58 in PDAC tissues were analyzed using various public databases. Then, the phenomenon of expressional separation of CD58 in PDAC cells induced by macrophages was observed by flow cytometry and ELISA, where the decrease of mCD58 on the membrane surface is accompanied by the increase of sCD58 in the supernatant. The molecular mechanisms of the expressional separation of CD58 were further explored by focusing on the TGF-β signaling pathway. The effects of expressional separation of CD58 on the immune activity and killing ability of T/NK cells for PDAC were determined in co-culture models. Furthermore, subcutaneous tumor-bearing models, lung metastasis models, and intraperitoneal dissemination models were used to confirm the in vitro data. Finally, the diagnostic and prognostic roles of serum sCD58 were determined by using 561 samples from PDAC patients, benign pancreatic disease patients, and healthy controls. Elevated CD58 expression in PDAC tissues was associated with worse clinical outcomes. After co-culture with PDAC cells, macrophages adopted an M2 phenotype, characterized by a high expression level of TGF-β. Co-cultured macrophages could induce the expressional separation of CD58 in PDAC cells. Activation of the TGF-β/Smad2/3 pathway markedly promoted this separation, and pathway inhibition largely blocked it. In vitro and in vivo assays revealed that mCD58 engaged CD2 on T/NK cells, facilitated their activation, enhanced their cytotoxicity, and stimulated the release of the anti-tumoral cytokines IFN-γ and TNF-α. Conversely, local high concentrations of sCD58 accumulation in PDAC tissues interfered with the CD2-CD58 axis by competitively binding CD2, inhibited the activation of T/NK cells, reduced T/NK cytotoxicity, and the secretion of IFN-γ and TNF-α. Furthermore, serum sCD58 levels were higher in the PDAC patients than in the healthy controls or patients with benign pancreatic diseases. sCD58 improved the diagnostic and prognostic power of CA199 in PDAC patients. A combined model incorporating CA199, TGF-β1, and sCD58 yielded an AUC (area under the curve) value of 0.946 for overall diagnosis. In the CA199 negative cohort, the combined model of TGF-β and sCD58 achieved an AUC of 0.955. This study uncovers a novel vicious crosstalk among macrophages, T/NK cells, and PDAC cells within the tumor microenvironment. Macrophages drive the expressional separation of CD58 via the TGF-β/Smad2/3 signaling pathway. This shift suppresses T/NK-cell activity, allows tumor cells to evade immune killing, and accelerates PDAC progression. In addition, serum sCD58 emerges as a promising diagnostic and prognostic biomarker for PDAC.
Zhang et al. (Mon,) studied this question.