Commentary: Small Molecule Inhibition of PD-1 Transcription is an Effective Alternative to Antibody Blockade in Cancer Therapy.

Abstract

The past few years has witnessed exciting progress in the application of “immune checkpoint inhibitors” (ICI) in the treatment of various human cancers1–3. This involves the use of antibody blockade with monoclonal antibodies (mAbs) that block receptor binding to their natural ligands. Programmed cell death-1 (PD-1) recognises PD ligand (PDL)-1 and PDL-2 on presenting cells and this sends signals that inhibit T-cell activation and effector cytotoxic responses. Through these mechanisms, PD-1 inhibits the immune system and can prevent autoimmune diseases 4. Tumor cells expressing PDL-1/PD-L2 can use this mechanism to evade immune surveillance, allowing disease progression. A therapeutic approach involves administration of mAbs that block the engagement of checkpoint molecules with their ligand. In the case of anti-PD-1, these mAbs block the binding of PD-1 on the T-cell with PDL-1/PDL-2 on the tumor cell, preventing recognition and allowing activation of the T-cell to provide an immune response against the tumor cell. Blockade also reverses T-cell exhaustion and restores T-cell functionality 5, 6. Furthermore, PD-1 expression on tumor-infiltrating CD8+ T-cells correlates with impaired function, while PDL1 expression on tumors facilitates escape4.