The ‘‘two-signal’’ model of T-cell activation, first requiring the interaction of T-cell receptor (TCR) with a major histocompatibility complex (MHC) molecule expressed by antigen presenting cells (APCs). To complete T-cell activation, the interaction of the CD28 receptor on T-cells with B7 co-stimulatory molecules (B7-1 and B7-2) on APCs is necessary. This phase occurs primarily within the lymph nodes. To prevent inappropriate T-cell activation, negative regulators of T-cell immunity, including CTLA-4 and PD-1, are required. CTLA-4 competes with CD28 for the interaction with B7, and it is upregulated shortly after T-cell activation. Anti-CTLA-4 antibodies, such as ipilimumab and tremelimumab, block CTLA4 and, thereby, enhance antitumor activity. The PD-1 inhibitory receptor plays an important role in modulating T-cell activity in the peripheral tissues during the effector phase. The ligation of PD-1 with PD-L1 causes the negative regulation of T-cells in the tumor microenvironment. Blockade with antibodies of PD-1 or PD-L1 (e.g., nivolumab and MK-3475) results in the activation of T-cells. TAA, tumor-associated antigen; NK, natural killer.