Immune checkpoint inhibitors and the shared epitope theory: from hypothesis to practice

Checkpoints are inhibitory receptors expressed on activated T cells. During the process of carcinogenesis, tumor cells progressively express multiple inhibitory receptor-ligands to prevent T cell recognition and elimination. Consequently, therapeutic blockade of these checkpoints, or their ligands, helps recover anti-tumor immunity. Checkpoint inhibitors have been considered as a new armory for cancer patients due to the broad effectiveness of three agents blocking the inhibitory receptors CTLA-4, PD-1, and PD-L1 (the ligand for PD-1) (1). Based upon prolonged overall survival in clinical trials, antibodies inhibiting CTLA-4, PD-1 and PD-L1 have been approved by the FDA for multiple clinical indications, including melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, urothelial carcinoma, renal cell carcinoma, Hodgkin lymphoma, and other adult and pediatric solid tumors.