Moreover, inactivating mutations in the nuclear receptor binding SET domain protein 1 (NSD1) a histone methyltransferase define an intrinsic subtype of HNSCC that features pronounced DNA hypomethylation [35,63,64] and displays an immune cold phenotype characterized by low levels of TILs and low expression of a CD8-positive T cell inflamed gene signature [65,66]. This evidence concerns the gene CD8A and head and neck squamous cell carcinoma.