The enhanced activity of ICIs in hypermutated lesions seems to rely on the higher rate of tumor-specific neoantigens which peculiarly characterizes these cancers; indeed, while the generation of a great multiplicity of neoantigens attracts a pronounced number of tumor-infiltrating lymphocytes (TILs) within tumor tissues, T cell antitumoral cytotoxic activity is negatively counterbalanced by the overexpression of immune checkpoints, such as PD-1 or PD-L1 [50]. The gene discussed is CD274; the disease is cancer.