Therapeutic Induction of MKP-1 Decreases M2 Macrophage Polarization

Objectives: Myeloid cells recruited at tumor sites are often instructed by the tumor microenvironment to acquire a pro-tumoral phenotype. Prior work from our laboratory indicates that Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1) deficiency alters macrophage propensity towards a tumor-promoting (M2) phenotype, suggesting that pharmacological induction MKP-1 could be a viable target to reprogram tumor associated-macrophages towards a tumor-killing (M1) phenotype. Herein, we explore the potential of MKP-1 pharmacological agonist, auranofin, to repolarize M2 macrophage populations.
Methods: The potential efficacy of an MKP-1 agonist, auranofin, to induce MKP-1 expression was evaluated in primary BMDMs culture and measured mRNA by qPCR. To test the therapeutic potential of a novel MKP-1 targeted agent to repolarize pro-tumoral macrophage phenotype, bone marrow-derived macrophages (BMDMs) were polarized to become M2 macrophages, exposed to auranofin or controls and then analyzed by flow cytometry for M1/M2 phenotype.
Results: Auranofin-treated BMDMs showed a significant dose- and time-dependent increase in MKP-1 expression. Further, we demonstrated that the exposure of M2 macrophages to auranofin significantly decreased the number of M2-specific marker CD206⁺ within the M2-activated macrophage population.
Conclusions: Initial studies support that MKP-1 targeted agent plays a role in macrophage polarization towards a reduced pro-tumoral M2 phenotype. These findings are a foundation to test the therapeutic effect of neoadjuvant therapy using this MKP-1 targeted agent in translational models of oral cancer.