CD274 and neoplasm: While tumor intrinsic factors are due to inability of immune recognition as observed with downregulation of PD-L1, an immune receptor induces T-cell anergy [83,84], down-regulation of antigen-presentation systems, and major histocompatibility complex (MHC) presentation, dysregulation of oncogenic pathways like p53, RAS/RAF/MAPK signaling and others; tumor extrinsic factors are due to resistance within tumor microenvironment (TME) and toward immunotherapy [84].