| Sumario: | Simple Summary: Head and neck cancers are categorized into two distinct types based on the presence of the human papillomavirus. While the protein known as macrophage migration inhibitory factor is recognized for promoting tumor growth and suppressing the immune system, its role as a marker for tracking disease progression has been unclear. This study monitored changes in this protein's levels over time in patients undergoing treatment. The findings reveal that in virus-negative patients, the protein levels consistently drop after successful treatment, making it a reliable tool for monitoring recovery. However, in virus-positive patients, the protein levels fluctuate unpredictably and may even decrease during cancer relapse, suggesting a much more complex role in the immune response. These results highlight that doctors must consider a patient's virus status when using immune markers to monitor cancer, potentially leading to more personalized follow-up care and better-informed clinical decisions. Background: Macrophage migration inhibitory factor (MIF) is a critical modulator of the tumor immune microenvironment (TME). Its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains controversial because of HPV-dependent tumor biology and the limitations of single-timepoint biomarker assessments. This preliminary study evaluates whether dynamic changes in circulating MIF (ΔMIF) in an HPV-stratified longitudinal cohort reflect disease severity and treatment response. Methods: Ninety-six serial serum samples were analyzed from 27 HNSCC patients (22 HPV-positive, 5 HPV-negative) from diagnosis through therapy and follow-up. Serum MIF and anti-HPV16 E7 IgG were quantified by ELISA, and ΔMIF was defined as the change in MIF concentration between consecutive visits. Results: Baseline MIF did not correlate with clinical stage in the total cohort (p = 0.63). However, 56% of HPV-positive patients exhibited a positive correlation between elevated MIF and advanced stage. Following chemoradiotherapy, the HPV-negative group showed a consistent and significant decline in MIF (mean ΔMIF = −1.23, p = 0.031), corresponding with no evidence of disease (NED). In contrast, the HPV-positive group showed heterogeneous trajectories (mean ΔMIF = +0.21, p = 0.94), with several patients demonstrating paradoxical declines in MIF during active disease or relapse, followed by recovery upon reaching NED. In select cases, MIF dynamics were closely synchronized with anti-E7 IgG levels. Conclusions: Serum MIF dynamics are strongly dependent on HPV status. While MIF serves as a reliable therapy-monitoring marker in HPV-negative HNSCC, it may play a complex and paradoxical immunomodulatory role in HPV-positive disease. These preliminary findings support the need for larger prospective, HPV-stratified trials.
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