Our finding that reduced frequency of CD8+CD28+ T cells as well as increased frequency of CD8+CD28− T cells are associated with poor prognosis, suggest that a progressive deterioration of intratumoral immune response, characterized by loss of memory T cells and functional exhaustion of effector T cell subsets, is a relevant pathogenic mechanism of tumor immune escape in HNSCC. Here, CD28 is linked to head and neck squamous cell carcinoma.