Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma.

Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) - a type of macrophages - in tumors from patients with HNSCC, which are associated with a favorable prognosis in treatment-naive and preoperative-chemotherapy-treated patients. Importantly, MGC density increased in tumors following preoperative therapy, suggesting a role of these cells in the anti-tumoral response. To enable clinical translation of MGC density as a prognostic marker, we developed a deep-learning model to automate its quantification on routinely stained pathological whole slide images. Finally, we used spatial transcriptomic and proteomic approaches to describe the MGC-related tumor microenvironment and observed an increase in central memory CD4 T cells. We defined an MGC-specific signature resembling to TREM2-expressing mononuclear tumor associated macrophages, which co-localized in keratin tumor niches.