Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway

Abstract

T-lymphocytes have the potential to recognize cancer antigens as foreign and therefore eliminate them. However, immune checkpoints such as cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and programmed cell death (PD)-1 receptor and its ligands (PD-L1, PD-L2) suppress the activity of T-lymphocytes. Advances in the understanding of immunology and its role in cancer have led to the development of immune checkpoint inhibitors that block CTLA-4 and PD-1 and result in durable responses in patients with a wide range of cancers. PD-1 and PD-L1 inhibitors are currently in many stages of clinical investigation, and the anti-PD-1 antibody, pembrolizumab, was recently approved by the US Food and Drug Administration. Many questions remain to be answered, such as the optimal administration schedule, biomarkers that associate with benefit, and potential for use of PD-1 agents in combination approaches. Nonetheless, immunotherapy with PD-1 blocking antibodies is now becoming an integral part in the management of cancer.

Keywords: cytotoxic T-lymphocyte antigen 4; immune checkpoints; immunotherapy; programmed cell death protein-1.

Figure 1

Simplified concept of CTLA-4 and PD-1 immune checkpoints. Notes: In the priming phase, antigen-presenting cells present antigens to the T-cell. Two signals are required to initiate a T-cell response. CTLA-4 is upregulated after T-cell activation and inhibits the T-cell response. Anti-CTLA-4 antibodies bind to CTLA-4, turning off the ‘inhibitory signal’, thus resulting in an enhancement of T-cell function. In the effector phase, the PD-1 inhibitory receptor is expressed by the T-cell and, when it is engaged by its ligands PD-L1 and PD-L2, it serves to inhibit the T-cell response. Anti-PD-1 antibodies bind to PD-1, turning off the ‘inhibitory signal’ in the peripheral tissues and enhancing T-cell function. PD-1/PD-L1 interactions are complex, and this interaction is also involved in the priming phase. We have chosen to portray the main concepts for both of these immunologic checkpoints in this figure for simplicity. Abbreviations: CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated antigen; MHC, major histocompatibility complex; PD, programmed cell death; TCR, T-cell receptor.