Critical differences between effector function in the periphery relative to the tumor. On the left: in lymph nodes, relatively low levels of cell activation and pro-inflammatory cytokines result in low levels of expression for most targets of immunomodulatory antibodies, which are generally low on resting immune cells. This low level of target expression, together with a paucity of effector cells in lymph nodes means depletion of cells through cell mediated effector functions do not readily occur. On the right: high levels of pro-inflammatory cytokines within the tumor microenvironment trigger up-regulation of many targets. This increased target expression together with a high density of effector cells, such as macrophages, enables depletion of cells through cell-mediated effector functions. The level of target expression, and the sensitivity to depletion varies across cell types and favours depletion of T-regs for targets such as CTLA-4 and GITR.