Dataset Information

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab.

ABSTRACT:

Background

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. 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.

Results

Here 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.

Conclusion

Due 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.

SUBMITTER: Roither B

PROVIDER: S-EPMC7734776 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab.

Roither Bernhard B Oostenbrink Chris C Schreiner Wolfgang W

BMC bioinformatics 20201214 Suppl 17

<h4>Background</h4>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. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the ...[more]

PMID: 33308148

Similar Datasets

Project description:ImportanceRobust predictors for response to anti-programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non-small cell lung cancer (NSCLC) are not fully characterized.ObjectiveTo evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC.Design, setting, and participantsThis multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Data were analyzed from December 2019 to February 2020.ExposuresSequential nivolumab was given on day 1 of a 14-day cycle. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1.Main outcomes and measuresOverall response rate (ORR) according to the PD-L1 copy number status. Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status.ResultsA total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less.Conclusions and relevanceIn this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. External validation with a larger sample size is warranted.

Dataset Information

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab.

Background

Results

Conclusion

Publications

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab.

Similar Datasets

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