Prognostic impact of HLA-G expression in cervical squamous cell carcinoma: correlation with PD-L1 and CD8-positive tumor infiltrating lymphocytes.

BACKGROUND: Purpose of the study was to investigate the prognostic impact of HLA-G expression in patients with cervical squamous cell carcinoma (CSCC), and to further analyze its correlations with PD-L1 and CD8-positive (CD8+) tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME). METHODS: A total of 139 formalin-fixed paraffin-embedded (FFPE) tissue samples were collected from patients diagnosed with CSCC. Immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) staining were performed to assess the expression of immune biomarkers, including HLA-G, its receptor ILT2, PD-L1, total TILs and CD8+ TILs. RESULTS: The overall positive expression rates were 86.8% for HLA-G, 85.1% for sHLA-G, 50.0% for PD-L1, and 70.2% for cases with low TIL infiltration in the TME. These immune biomarkers displayed distinct immunoreactivity patterns with remarkable intratumoral and stromal heterogeneity. ILT2 expression was positively correlated with CD8+ TIL infiltration in both intratumoral and stromal compartments, yet rare cellular co-localization between ILT2 and CD8 was detected. Within tumoral regions, a strong positive correlation was identified between HLA-G and PD-L1 expression, and the two proteins were confirmed to be co-localized at the single-cell level in SCC lesions. Using the median HLA-G expression level of 61.0% as the cutoff value, patients with HLA-G expression above this threshold showed significantly worse overall survival (OS). The subgroup with high HLA-G/sHLA-G and low TIL infiltration showed the worst prognosis. CONCLUSIONS: The present study confirms that elevated HLA-G/sHLA-G expression serves as an independent adverse prognostic factor for cervical cancer. Combined assessment of HLA-G, PD-L1 and TIL infiltration may enable risk-stratified prognostic management for patients with cervical cancer.