The Relationship of CD4+, CD8+, and FOXP3+ Tumor-Infiltrating Lymphocytes and Their Ratios With Clinicopathological Parameters and Tumor Budding in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma is the most common histological subtype of esophageal cancer, and novel therapeutic strategies, including immunotherapy, are increasingly needed to improve outcomes in advanced-stage disease. Identifying patients who may benefit from immunotherapy through individualized risk stratification and reliable prognostic biomarkers is therefore essential. This study aims to evaluate the association between tumor-infiltrating lymphocyte (TIL) subtypes (CD4 ⁺ , CD8 ⁺ , FOXP3 ⁺ ) and their ratios, with clinicopathological features, and tumor budding.

The study included 75 patients diagnosed with esophageal squamous cell carcinoma who underwent esophagectomy without receiving preoperative neoadjuvant therapy. Sections best representing the tumor area and TILs were selected, and immunohistochemical staining for CD4, CD8, and FOXP3 was performed. Positive lymphocytes were counted in 10 high-power fields at the invasive front. TIL densities were categorized as low or high based on mean counts. Tumor budding was assessed and classified as low, intermediate, or high grade.

According to our results, low CD4 ⁺ TIL levels were significantly associated with poor histological grade, deeper tumor invasion, advanced pathological stage, and low tumor budding. High FOXP3 ⁺ TIL expression was associated with invasion depth and lymph node metastasis, whereas superficial tumors showed no high FOXP3 expression. A low FOXP3 ⁺ /CD4 ⁺ ratio was correlated with longer survival. CD8 ⁺ TIL density alone showed no significant prognostic impact.

In conclusion, combined assessment of TIL subtypes and tumor budding may contribute to improved prognostic stratification and postoperative treatment planning in esophageal squamous cell carcinoma.