CD3 and PD-L1 tissue expression have synergistic value in head and neck squamous cell carcinoma prognosis

• CD3 high and PD-L1 CPS ≥ 1 each predict better OS and RFS in HNSCC. • Best outcomes seen in patients with both CD3 high and PD-L1 CPS ≥ 1. • Combined markers outperform either marker alone for prognosis. • Markers may help identify patients with favorable prognosis under standard care. • Predictive value for immunotherapy remains to be clarified. T cell infiltrates, particularly CD3 + T cells, have been linked to a favorable prognosis in cancer. However, the influence of PD-L1 expression on survival remains controversial, particularly in patients who do not receive immune checkpoint inhibition. This goal of this study was to combine CD3 density and PD-L1 expression to assess their individual and combined prognostic value in head and neck squamous cell carcinoma (HNSCC) patients treated with surgery and adjuvant therapy. A tissue microarray of 458 HNSCC primary tumor samples was analyzed for CD3 and PD-L1 expression using multiplex immunohistochemistry. CD3 densities were quantified using digital image analysis (QuPath), and PD-L1 expression was categorized by the Combined Positive Score (CPS). Overall survival (OS) and recurrence-free survival (RFS) were calculated and compared across different expression profiles using the Kaplan-Meier method followed by a multivariate cox regression analysis. CD3 high tumors (defined as greater the median CD3 expression) were associated with longer OS and RFS compared to CD3 low tumors (below median). Similarly, PD-L1 expression at CPS ≥ 1 was linked to significantly better survival outcomes than CPS < 1. The combination of CD3 high and PD-L1 CPS ≥ 1 showed the most favorable prognosis. The combined assessment of CD3 density and PD-L1 expression outperforms either marker alone in predicting survival outcomes in surgically treated patients without immunotherapy. CD3 high and PD-L1 CPS ≥ 1 identifies patients with favorable prognosis and response to standard-of-care treatment. Nonetheless, the potential relevance of these markers for guiding immunotherapy in other setting remains to be explored.