CTLA4 and neoplasm: Immunosuppressive cytokines/factors and cells in the TME in the presence of persistent tumor antigen stimulation induce prolonged and increased expression of cell surface IRs including, CTLAntigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1), Mucin-3/T-cell immunoglobulin (TIM-3), T-cell activation gene (LAG-3) and T-cell tyrosine-based inhibitory motif (ITIM) on TILs [36] (Figure 2).