Fig. 2.

Mechanism of PD-1 immunosupression as a target for cancer therapy. (Modified from Refs [31–33]. Clin Cancer Res. 2012;18: 6580–6587, Nat Rev Cancer. 2012;12: 252–264; Nat Immunol. 2013;14: 1212–1218).

PD-1 is expressed on the surface of effector T cells upon activation, and its ligand, PD-L1 is expressed on the tumor cells either by constitutive oncogenic signaling or by the induction in response to inflammatory signals as a response to tumor. The binding of PD-L1 to PD-1 delivers an inhibitory signal, through the phosphatase SHP2, which reduces cytokine production and proliferation of T cells, thus enabling tumor cells to evade the host immune response. Antibodies against PD-1 or PD-L1 prevent the binding and block immune inhibition by tumor, inducing anti-tumor immune response. Multiple additional receptor-ligand interactions that regulate T cell responses in the tumor microenvironment have been identified, such as KIR (killer cell immunoglobulin-like receptor), LAG3 (lymphocyte activation gene 3), and TIM3 (T cell membrane protein 3), and are currently under active investigation as possible targets for cancer immunotherapy.