HLA-DR Expression in paired Tumor Cells and CAFs of HPV-Negative Oral Squamous Cell Carcinoma: HLA-DR in epithelial and CAF cultures from HPV-neg OSCC reveals new immune features

Objective: Oral squamous cell carcinoma (OSCC) responds poorly to standard therapies, while immunotherapy is emerging as a promising alternative. Identifying immune-related biomarkers may improve patient stratification. We previously showed that HNSCC epithelial cells can express HLA-DR, a class II MHC molecule. Here, we investigated HLA-DR expression in relation to the tumor microenvironment, focusing on cancer-associated fibroblasts (CAFs), and its association with PD-L1. Methods: Biopsies from five OSCC patients were used to isolate epithelial tumor cells, CAFs, and normal fibroblasts. HLA-DR expression was analyzed by flow cytometry. TCGA datasets were examined to compare HLA-DR and PD-L1 expression in normal tissues and HNSCC and to assess their correlation. Results: OSCC epithelial cells exhibited de novo HLA-DR expression. Both CAFs and normal fibroblasts expressed HLA-DR, with significantly higher levels in CAFs. TCGA analyses confirmed increased HLA-DR and PD-L1 expression in HNSCC tissues and revealed a positive correlation between the two markers. Conclusions: The OSCC tumor microenvironment may promote HLA-DR expression in both epithelial tumor cells and CAFs. The association between HLA-DR and PD-L1 highlights a novel immunological feature of OSCC with potential relevance for immunotherapy-based strategies.