Recent studies have further highlighted the multiple involvement of peripheral CD4+T-cells in both innate and adaptive immune response (20–22), enhancing the antigen presentation machinery, increasing CD8+T-cell effector differentiation (21, 23), expressing even direct cytotoxic activity (24), driving B-cell activation and antibody affinity maturation (20–22), sustaining the immune surveillance during melanoma evolution via targetable checkpoint molecules (20–22, 25). The gene discussed is CD4; the disease is melanoma.