In patients with metastatic melanoma, functionally impaired/exhausted, NK cells upregulated TIM-3 in NK cells compared to healthy subjects, and TIM-3 blockade in vitro reversed this exhausted phenotype.541 In T-cells, TIM-3 engagement with ligands leads to the phosphorylation of two tyrosines in its cytoplasmic tail (Y256 and Y263), leading to the dissociation of HLA-B associated transcript-3 (Bat-3). This evidence concerns the gene HAVCR2 and metastatic melanoma.