Abstract
BackgroundThe immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the immunosuppressive interaction with PD-L1. Even though PD-1 is already used as a drug target, the exact mechanism of the receptor is still a matter of debate. For instance, it is hypothesized that the signal transduction is based on an active conformation of PD-1.ResultsHere we present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain with a focus on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. We could demonstrate that the BC-loop can form three conformations. Nivolumab binds to the BC-loop according to the conformational selection model whereas PD-L1 induces allosterically a conformational change of the BC-loop.ConclusionDue to the structural differences of the BC-loop, a signal transduction based on active conformation cannot be ruled out. These findings will have an impact on drug design and will help to refine immunotherapy blocking antibodies.
Highlights
The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy
The immune checkpoint receptor Programmed cell death protein I (PD-1) has been identified as a key target in cancer immunotherapy
The PD-1 blocking antibody nivolumab which inhibits the Programmed cell death protein I ligand I (PD-L1) binding was recently approved by the FDA
Summary
The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. Programmed cell death protein I (PD-1) is a type 1 transmembrane protein in mainly T and B cells and a so-called immune checkpoint as it promotes self-tolerance by inducing apoptosis of antigen-specific T cells, a mechanism which is often exploited by cancer cells. Cancer cells which express PD-L1 evade the host immune system by inducing apoptosis in cancer antigen specific T cells [4]. Nivolumab is clinically used for the treatment of melanoma, metastatic renal cell carcinomas, classical Hodgkin lymphoma (cHl) and non-small-cell lung carcinoma (NSCLC) [5]
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