Agonistic SLAMF7 signaling, in synergy with TCR activation, is able to strongly induce T-cell activation and clonal expansion, a finding consistently observed in CD8+ T cells from healthy adults as well as derived from blood and tumor-draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC). Here, SLAMF7 is linked to head and neck squamous cell carcinoma.