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 as current risk-management and treatment strategies are suboptimal; yet novel prognostic biomarkers are generally difficult to integrate into clinical practice. 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 facilitate 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 defined an MGC-specific RNA signature using spatial transcriptomics and found a close resemblance to TREM2-expressing mononuclear tumor-associated macrophages, which co-localized with MGC in keratin-rich tumor niches and were associated with a good response to neoadjuvant immunotherapy.