The Molecular Mechanism Of TKIs-Biomechanics Tuning The Interaction Of PD-1 And PD-L1

Cancer cells can evade or suppress immune responses by activating inhibitory immune checkpoint proteins,such as PD-1 and PD-L1.Blocking the interaction between PD-1 and PD-L1with monoclonal antibodies to restore immune cell function,has delivered a huge breakthrough in clinical immunotherapy against cancer.However,the response rate to PD-1 or PD-L1 antibody remains at 15%-30%as a single agent and even lower in some diseases,such as in colorectal cancer.Moreover,many patients who received anti-PD-1 or anti-PD-L1 therapy have a high risk of developing autoimmune disorders.Therefore,it is essential that an in-depth understanding of the characteristics of PD-1 and PD-L1 interaction and its regulatory mechanism in order to predicting the patient's effective response,possible adverse reactions and therapeutic effects.This study combined single-molecule biophysical approaches,molecular dynamics and biochemistry methods to collectively demonstrate that EGFR-TKIs coupling with biomechanical tune the interaction of PD-1 and PD-L1.Intriguingly,EGFR-TKIs inhibit the phosphorylation of PD-L1 in intracellular domain resulting in the low affinity of PD-1 and PD-L1.Furthermore,EGFR-TKI regulate the phosphorylation of PD-L1 through GSK3a.And EGFR-TKIs coupling biomechanics regulate the interaction of PD-1 and PD-L1.Our findings not only reveal the molecular regulation mechanism of the interaction of PD-1 and PD-L1 but also have implications for the PD-1 or PD-L1-based immunotherapy.