Heterogeneity and plasticity of tumor-associated macrophages in oral squamous cell carcinoma: implications for diagnosis and tumor microenvironment characterization.

BACKGROUND

Oral squamous cell carcinoma (OSCC) is the predominant histological subtype of oral cavity cancers, with a 5-year survival rate of approximately 50%. The tumour microenvironment, particularly macrophage infiltration and polarization, plays a critical role in tumour progression and patient prognosis. Models describing macrophages as either M1 (pro-inflammatory) or M2 (anti-inflammatory) are increasingly recognized as oversimplified, given the functional heterogeneity and plasticity of tumour-associated macrophages (TAMs). This study aims to evaluate the expression of macrophage markers CD68, CD163, CD11c, and CD115 in OSCC compared to normal oral mucosa (NOM), to assess their diagnostic and prognostic value.

METHODS

A cross-sectional study of 179 tissue samples (111 OSCC, 68 controls) analysed macrophage markers (CD68, CD163, CD11c, CD115) via real-time qPCR. Statistical tests included Mann-Whitney U, ROC analysis for diagnostic utility, Spearman's ρ for correlations, and assessments of associations with prognosis and recurrence. Cut-offs for gene overexpression were based on ROC results and evaluated clinically.

RESULTS

All four markers showed significantly higher expression in OSCC compared to NOM (p < 0.001 for CD68, CD163, CD11c; p = 0.001 for CD115). ROC analyses demonstrated diagnostic AUCs of 0.69 (CD68), 0.78 (CD163), 0.81 (CD11c), and 0.66 (CD115), indicating poor, fair and good discriminative capacity, respectively. Overexpression of the genes defined by COP was significantly associated with malignancy (p < 0.01). Elevated CD68 and CD163 levels correlated with higher tumour grading (G2/G3), while increased CD11c expression was linked to nodal metastasis (p = 0.04). Strong positive correlations existed between CD115 and the other markers (ρ > 0.61, p < 0.001), supporting a model of macrophage heterogeneity and plasticity. Concurrent upregulation of pro-inflammatory (CD11c) and M2-associated (CD163) markers suggests a complex, dynamic TAM landscape rather than a simple M1/M2 dichotomy.

CONCLUSIONS

Altered RNA expression of the macrophage cell surface markers CD115, CD68, CD163 and CD11c in OSCC, and their respective association with tumour grading, N-status and perineural sheath infiltration, may serve as a basis for future single-cell sequencing or immunohistological - multiplex immunofluorescence - studies. Further investigation of these markers could lead to promising insights into the modulation of the tumour immune microenvironment.