PD-L1 expression patterns in stage IB1 cervical squamous cell carcinoma: a retrospective study on implications for tumor budding and immune microenvironment.

[BACKGROUND] The immune microenvironment at the tumor invasion front plays a pivotal role in cancer progression. Tumor budding, an aggressive histopathological feature, has been linked to poor outcomes in various malignancies. However, its impact on the tumor immune microenvironment remains poorly understood. This retrospective study aimed to determine whether tumor budding is a risk factor for lymph node metastasis (LNM) in stage IB1 cervical squamous cell carcinoma (CSCC) and to explore the relationship between PD-L1 expression in tumor cells and CD8 and FOXP3 tumor-infiltrating lymphocytes (TILs) within tumor budding regions.

[METHODS] Tumor budding was retrospectively evaluated in 106 cases of International Federation of Gynecology and Obstetrics (FIGO) (2009) stage IB1 CSCC. High-grade tumor budding was defined as ≥ 15 buds per 10 high-power fields (HPFs). Immunohistochemistry was used to detect PD-L1, CD8, and FOXP3 expression. CD8 T cells and FOXP3 regulatory T cells (Tregs) were quantified separately intraepithelial and stromal compartments.

[RESULTS] High-grade tumor budding was identified in 48 cases (45.3%) and was significantly associated with lymph node metastasis (LNM) on univariate analysis; however, it was not an independent predictor of LNM on multivariable logistic regression analysis. PD-L1 expression was detected in 53.8% (57/106) of the cohort, with overexpression observed in tumor budding areas. Three distinct PD-L1 expression patterns were identified: diffuse, marginal/tumor budding (MT), and negative. Notably, tumors with MT PD-L1 expression exhibited more favorable clinicopathological features compared to those with diffuse PD-L1 expression, including smaller tumor size, well differentiation, and low-grade tumor budding. In terms of the tumor immune microenvironment, PD-L1-negative tumors exhibited sparse infiltration of CD8 T cells and FOXP3 Tregs, whereas tumors with the MT pattern showed abundant stromal infiltration of both cell types. In contrast, diffuse PD-L1 expression was associated with abundant stromal and intraepithelial infiltration of CD8 T cells and FOXP3 Tregs.

[CONCLUSIONS] High-grade tumor budding is associated with LNM in stage IB1 CSCC. Three distinct PD-L1 expression patterns within tumor budding areas are associated with clinicopathologic features and immune cell infiltration profiles. PD-L1 expression patterns may warrant further investigation as potential biomarkers for immunotherapy response.