CCL5 at the tumor-bone interface: A lymphocyte-derived gatekeeper against mandibular invasion in oral squamous cell carcinoma

OBJECTIVES: Mandibular bone invasion (MBI) in oral squamous cell carcinoma (OSCC) reflects advanced disease and poor prognosis. The role of the tumor immune microenvironment (TME) in MBI remains incompletely defined. We investigated the prognostic relevance of CCL5 and its association with bone invasion. MATERIALS AND METHODS: CCL5 mRNA expression was analyzed in the TCGA HNSCC cohort (n = 327) across T stages and correlated with overall survival (OS). Single-cell RNA sequencing data were used to identify the cellular sources of CCL5. Protein expression of CCL5 and FoxP3 was assessed by immunohistochemistry in a retrospective cohort of 206 OSCC patients using tissue microarrays, distinguishing tumor and TME compartments. Systemic inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], C-reactive protein-to-albumin ratio [CAR]) were also evaluated. RESULTS: CCL5 mRNA expression decreased with increasing T stage and was lowest in T4a tumors with bone invasion (p = 0.038). High CCL5 levels were associated with improved OS (p = 0.026). Single-cell analysis identified CD8⁺ T cells, regulatory T cells, and natural killer cells as principal sources of CCL5. In the clinical cohort, low CCL5 and FoxP3 expression in the TME correlated with MBI (p = 0.008 and p < 0.001). Multivariable analysis confirmed high CCL5 expression in the TME as an independent predictor of favorable OS (HR = 0.294, p = 0.015), whereas high NLR predicted poor survival (HR = 2.664, p = 0.044). CONCLUSIONS: A CCL5- and FoxP3-deficient TME characterizes bone-invasive OSCC and independently predicts poor survival, supporting their value as biomarkers for risk stratification.