The limited clinical efficacy of therapeutic vaccines for HPV+ HNSCC, especially in the monotherapy setting, can also be explained by the fact that, even if anti-tumor responses are elicited, the primed or re-primed CD8+ T cells will eventually encounter negative immunoregulatory signals in the TME such as PD-L1 and other immunoregulatory cell subsets such as regulatory T cells and myeloid suppressor cells, thus blunting their activity [157]. The gene discussed is CD8A; the disease is head and neck squamous cell carcinoma.