TROP2 expression in head and neck squamous cell carcinoma: association with the tumor immune microenvironment and clinical outcome.

INTRODUCTION: TROP2 is a transmembrane glycoprotein implicated in tumor progression and immune regulation across epithelial malignancies and serves as a therapeutic target for antibody -drug conjugates. Its role in the tumor immune microenvironment of head and neck squamous cell carcinoma (HNSCC), particularly in the context of PD-1 blockade, remains insufficiently defined. METHODS: TROP2 protein expression was assessed by immunohistochemistry in 47 patients with HNSCC treated with anti -PD-1 therapy, including primary tumors and, in 27 cases, matched recurrent and/or metastatic lesions. Expression was quantified using the immunoreactive score. Tumor-infiltrating immune cells (CD3, CD8, CD4, FOXP3, CCR4, and CD163) were analyzed in intra- and peritumoral compartments. In parallel, transcriptomic data from The Cancer Genome Atlas (TCGA; n = 483) were evaluated to explore associations between TROP2 mRNA expression and immune infiltration signatures. RESULTS: TROP2 expression was detected in 95% of tumors, with more than 80% showing moderate to high levels. Higher TROP2 expression was significantly associated with lower T status and showed a trend toward absence of distant metastasis but was not associated with nodal status, UICC stage, disease setting, or response to PD-1 blockade. Increased intratumoral CCR4+ and CD3+ T-cell infiltration correlated with improved survival. TCGA analysis demonstrated significant associations between TROP2 expression and multiple immune cell populations, including CD8+ and CD4+ T cells, Th2 cells, dendritic cells, macrophages, and TGF-β -related signatures. DISCUSSION: These findings indicate that TROP2 is broadly expressed in HNSCC and linked to distinct immune microenvironment features, supporting its potential as a therapeutic target.