The tumor intrinsic factors of primary resistance identified so far include 1) alterations in the antigen processing pathway; 2) a lack of tumor antigen expression; 3) the soft- and hard-wired loss of HLA expression; 4) alterations in the signaling pathways of MAPK, PI3K and WNT; 5) the constitutive expression of the ligands for IC (e.g., PD-L1 and HLA-E); and 6) resistance to TNF-α and IFN-γ mediated killing [75,76]. The gene discussed is HLA-E; the disease is neoplasm.