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Medical Communication

Immuno-oncology

The PD-1, PD-L1/PD-L2 pathway

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The body’s immune system is capable of detecting and destroying tumour cells.1-3 

The anti-tumour immune response occurs through various mechanisms, including the activation of T-cells.1-4
 

Figure 1. Simplified schematic diagram of the possible T-cell anti-tumour immune response pathway.1-15

During the anti-tumour immune response process:

  • Tumour cells express a multitude of tumour antigens.2-7
  • Antigen-presenting cells (APCs) capture and process the tumour antigens.5,7-9 APCs may include dendritic cells, macrophages, etc.7
  • These APCs migrate to the lymph nodes.5
  • In the lymph node, the mature APCs presents the antigenic peptides (which are now bound to the major histocompatibility complex (MHC) molecule) to the T-cells.5,7,10-12
  • Through the interaction of specific T- cell receptor and the MHC-bound antigenic peptide on the APC, the T-cell recognises the antigenic peptide and are activated.5,7
  • The activated T-cells proliferate, exit the lymph node and migrate to the tumour cells.5,7,13,14 The activated T-cells are able to eliminate the tumour cells.4,5,7,14,15
     

Some tumour cells are however able to evade the immune response.1,3,5 There are various “immune checkpoints” which limit the anti-tumour immune response.1,3,5,16  The programmed death-1 (PD-1) pathway is one of the key pathways that tumour cells can use to disrupt the cytotoxic activity of T-cells.1,3,5,16

 

Figure 2. Simplified schematic diagram of the possible evasion of the T-cell mediated immune response by the tumour cell, through the PD-1 pathway.1-3,5,16-18

To evade the immune response through the PD-1 pathway:

  • After an encounter with the antigens, PD-1 receptors are expressed on the surface of T-cells.16-18
  • The ligand to PD-1 (PD-L1) is overexpressed on the tumour cell’s surface.1,3,5,16
  • When the PD-1 receptor on the T-cell binds with the PD-L1 on the tumour cell, it results in the inhibition of the T-cell’s cytotoxic function against the tumour cell.2,3,5,16,17
  • The suppression of the T-cell’s function, through this PD-1 pathway, allows the tumour cells to survive.3,5,16

 

However, the antagonistic monoclonal antibodies such as anti-PD-1 (that binds to the PD-1 receptor) or anti-PD-L1 (that binds to PD-L1), prevent PD-1 and PD-L1 from binding to each other.1,16,19 Blocking this PD-1 pathway with anti-PD-1 or anti-PD-L1 allows the T-cell to retain its anti-tumour immune activity and these immune checkpoint inhibitors may augment the anti-tumour immune response.1,16,19-21

 

Figure 3. Simplified schematic diagram of the interaction of PD-1 and its ligands on the APC and T-cells, and subsequent inhibition by mAbs.1,16,20

Furthermore, the ligands to PD-1 (PD-L1 and PD-L2) are also expressed on APCs (such as dendritic cells and macrophages) and by binding with the PD-1 receptors on T-cells, can also inhibit T-cell function.1,16,20 This provides another target in the PD-1 pathway for immune checkpoint blockade inhibitors.20

 

By blocking the PD-1 pathway, anti-PD therapy assists in preventing the tumour cells from evading the anti-tumour immune response.21