The Tautomerase Activity of Tumor Exosomal MIF Promotes Pancreatic Cancer Progression by Modulating MDSC Differentiation

• Published in: Cancer immunology research 2024-01, Vol.12 (1), p.72-90
• Main Authors: Jia, Xuebing, Xi, Jianbei, Tian, Binle, Zhang, Yuanyuan, Wang, Zhilong, Wang, Fan, Li, Zheng, Long, Jiang, Wang, JianFei, Fan, Guo-Huang, Li, Qi
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cell Line, Tumor; Humans; Intramolecular Oxidoreductases - genetics; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Mice; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Tumor Microenvironment
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-23-0205

Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes (TDE) contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSC) within the pancreatic cancer TME. However, the underlying mechanisms remain elusive. Herein, we report that macrophage migration inhibitory factor (MIF) in TDEs has a key role in inducing MDSC formation in pancreatic cancer. We identified MIF in both human and murine pancreatic cancer-derived exosomes. Upon specific shRNA-mediated knockdown of MIF, the ability of pancreatic cancer-derived exosomes to promote MDSC differentiation was abrogated. This phenotype was rescued by reexpression of the wild-type form of MIF rather than a tautomerase-null mutant or a thiol-protein oxidoreductase-null mutant, indicating that both MIF enzyme activity sites play a role in exosome-induced MDSC formation in pancreatic cancer. RNA sequencing data indicated that MIF tautomerase regulated the expression of genes required for MDSC differentiation, recruitment, and activation. We therefore developed a MIF tautomerase inhibitor, IPG1576. The inhibitor effectively inhibited exosome-induced MDSC differentiation in vitro and reduced tumor growth in an orthotopic pancreatic cancer model, which was associated with decreased numbers of MDSCs and increased infiltration of CD8+ T cells in the TME. Collectively, our findings highlight a pivotal role for MIF in exosome-induced MDSC differentiation in pancreatic cancer and underscore the potential of MIF tautomerase inhibitors to reverse the immunosuppressive pancreatic cancer microenvironment, thereby augmenting anticancer immune responses.