However, at the same time in the tumor microenvironment, where the persistence of antigen and inflammation occurs, IFN-γ can upregulate immune checkpoint ligands, such as PD-L1 on cancer cells that leads CD8+ T cells to enter a state called “T cell exhaustion.” Exhausted CD8+ T cells increase the expression of immune checkpoint receptors, such as PD-1, LAG3, and TIM3, as well as loss of cytokines, such as IFN-γ and TNF-α, production in a hierarchical manner and lose their effector function by time (27). This evidence concerns the gene CD8A and cancer.