Tumor-Associated Macrophage Reprogramming to Improve Oral Cancer Therapeutic Efficacy

Objectives: The tumor microenvironment (TME) is a key component of oral squamous cell carcinoma (OSCC) as chronic inflammation associated with TME contributes to tumor progression. Tumor associated macrophages (TAMs) are associated with OSSC to promote the release of pro-inflammatory factors that are essential in malignant transformation. Dual specificity MAPK (MKPs) deactivate MAPKs. p38 MAPK, which is negatively controlled by MKP-1 through dephosphorylation of activated p38 MAPK, can support tumor progression and is activated in nearly 80% of OSCCs. The project laboratory has shown that these changes in TAMs polarize these myeloid lineage cells to become a M2 phenotype, which contributes to tumor growth more than M1 due to enhanced immunosuppressive function. Thus, the p38/MKP-1 signaling pathway may be a critical checkpoint that can be targeted with drug modulative therapy as a novel approach to OSCC therapy. Auranofin, an FDA-approved class of disease-modifying antirheumatic drug (DMARD) and known MKP-1 agonist, is traditionally prescribed as an anti-inflammatory agent to treat rheumatoid arthritis. Our goal is to determine if we can repurpose auranofin to increase MKP-1 that would in turn decrease p38 MAPKs.
Methods: We tested the therapeutic potential of a macrophage-directed neoadjuvant target Dusp1/MKP-1 to change in TAM polarization to a more predominate M1/M2 profile. RNAscope in situ hybridization (ISH) was employed to quantitate and spatially visualize M1/M2-associated mRNAs to complement ongoing efforts using flow cytometry to understand macrophage-directed neoadjuvant target Dusp1/MKP-1 to change TAM polarization.
Results: In RNAScope analysis, a Welch’s unequal variances t-test was performed to show that Mrc1 (CD 206; M2 marker) is decreased and Dusp1 (MKP-1) is increased in samples treated with auranofin with statistical significance.
Conclusions: These data suggest that MKP-1 targeted agents can repolarize TAMs to an M1 profile supporting tumor suppression.