Upregulation of PD-L1 and MMP9 in HR-HPV-associated cervical squamous cell carcinoma: correlation with histological progression and immune microenvironment remodeling

OBJECTIVE: To investigate the expression and significance of programmed death-ligand 1 (PD-L1), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinases 3 (TIMP3) in HR-HPV-associated cervical squamous cell carcinoma (CSCC) and precancerous lesions. METHODS: A retrospective analysis of 180 cervical cancer and lesion cases were performed, dividing them into a HR-HPV infection group (n=120) and a non-infection group (n=60). Immunohistochemical staining was used to assess the expression of PD-L1, MMP9, and TIMP3 proteins in both groups. RESULTS: PD-L1 and MMP9 expression was significantly higher in HR-HPV-infected specimens compared to non-infected ones across all lesion grades (P<0.05). Both markers exhibited progressive upregulation correlating with increasing lesion severity from inflammation to low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and CSCC. Quantitative analysis showed significantly higher integrated optical density values of PD-L1 and MMP9 in HR-HPV-positive HSIL and CSCC compared to HR-HPV-negative cases (P<0.05). In carcinoma patients, PD-L1 expression was correlated with HR-HPV infection status and histological grade (P<0.05), while TIMP3 showed an inverse correlation with MMP9 (r=-0.348, P=0.028). ROC analysis demonstrated superior diagnostic performance for PD-L1 (AUC=0.863) and MMP9 (AUC=0.731) compared to TIMP3 (AUC=0.175) in distinguishing CSCC from non-malignant lesions. CONCLUSION: The expression rates of PD-L1 and MMP9 increased progressively with lesion severity from inflammation through LSIL, HSIL, to CSCC. Additionally, higher-grade cervical squamous cell carcinoma exhibited stronger PD-L1 positivity in HR-HPV-infected cases.