Association of Macrophage Migration Inhibitory Factor (MIF) with Therapy Response and Clinical Outcomes in HPV-Related Head and Neck Squamous Cell Carcinoma: A Preliminary Report.

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.