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PD-1/PD-L1 in Cancer Immunotherapy 2022
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PD-1/PD-L1 in Cancer Immunotherapy 2022

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 13810

Special Issue Editor

Dr. Naoe Taira Nihira

E-Mail Website
Guest Editor
Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan
Interests: immunocheckpoints; cellular signalling; DNA damage response; post-translational modifications and p53 tumor suppressor

Special Issue Information

Dear Colleagues,

Cancer immune surveillance is an essential feature of cancer cells in vivo; therefore, immune checkpoint blockade is a promising therapeutic strategy. Indeed, clinical trials have shown that therapeutic antibodies against PD-1/PD-L1 have had favorable outcomes. Further, combination treatment with PD-1/PD-L1 blockade and molecular targeted drugs or anticancer agents is currently ongoing to increase therapeutic efficacy. Molecular-based studies for PD-1/PD-L1 functions and their regulatory mechanisms might contribute to discovering new molecular targeted drugs. Recently, research has focused on the intracellular functions of PD-L1, e.g., mRNA stability, transcriptional regulation, regulation of STAT signaling and the mTOR/Akt pathway and DNA damage response. In addition to PD-L1, intrinsic PD-1 expressed on tumor cells negatively regulates the Akt and ERK1/2 pathways. Thus, elucidation of the intracellular functions of PD-1/PD-L1, not limited to the function of plasma membrane as a ligand for PD-1, is a hot topic in PD-1/PD-L1 research. This Special Issue, entitled “PD-1/PD-L1 in Cancer Immunotherapy 2022”, aims to provide a research platform for the collection of the latest original and review articles focusing on intracellular functions of PD-1/PD-L1 in tumor cells.

Dr. Naoe Taira Nihira
Guest Editor

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Keywords

  • tumor cell-intrinsic PD-L1
  • immune checkpoint
  • cancer immunity

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Published Papers (4 papers)

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Research

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23 pages, 6321 KiB  
Article
Is the Triggering of PD-L1 Dimerization a Potential Mechanism for Food-Derived Small Molecules in Cancer Immunotherapy? A Study by Molecular Dynamics
by Xiaoyan Wu, Na Wang, Jianhuai Liang, Bingfeng Wang, Yulong Jin, Boping Liu and Yang Yang
Int. J. Mol. Sci. 2023, 24(2), 1413; https://doi.org/10.3390/ijms24021413 - 11 Jan 2023
Cited by 9 | Viewed by 2934
Abstract
Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules [...] Read more.
Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein–ligand complexes in solution, in which the 4′-hydroxy-3′-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy. Full article
(This article belongs to the Special Issue PD-1/PD-L1 in Cancer Immunotherapy 2022)
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18 pages, 8687 KiB  
Article
Approaching the Dimerization Mechanism of Small Molecule Inhibitors Targeting PD-L1 with Molecular Simulation
by Jianhuai Liang, Bingfeng Wang, Yang Yang, Boping Liu and Yulong Jin
Int. J. Mol. Sci. 2023, 24(2), 1280; https://doi.org/10.3390/ijms24021280 - 9 Jan 2023
Cited by 10 | Viewed by 2471
Abstract
Inhibitors blocking the PD-1/PD-L1 immune checkpoint demonstrate impressive anti-tumor immunity, and small molecule inhibitors disclosed by the Bristol-Myers Squibb (BMS) company have become a hot topic. In this work, by modifying the carbonyl group of BMS-202 into a hydroxyl group to achieve two [...] Read more.
Inhibitors blocking the PD-1/PD-L1 immune checkpoint demonstrate impressive anti-tumor immunity, and small molecule inhibitors disclosed by the Bristol-Myers Squibb (BMS) company have become a hot topic. In this work, by modifying the carbonyl group of BMS-202 into a hydroxyl group to achieve two enantiomers (MS and MR) with a chiral center, we found that this is an effective way to regulate its hydrophobicity and thus to reduce the negative effect of polar solvation free energy, which enhances the stability of PD-L1 dimer/inhibitor complexes. Moreover, we studied the binding modes of BMS-200 and BMS-202-related small molecule inhibitors by molecular dynamics simulation to explore their inhibitory mechanism targeting PD-L1 dimerization. The results showed that the size exclusion effect of the inhibitors triggered the rearrangement of the residue ATyr56, leading to the formation of an axisymmetric tunnel-shaped pocket, which is an important structural basis for improving the binding affinity of symmetric inhibitors with PD-L1. Furthermore, after inhibitor dissociation, the conformation of ATyr123 and BMet115 rearranged, which blocked the entrance of the binding pocket, while the reverse rearrangements of the same residues occurred when the PD-L1 monomer was complexed with the inhibitors, preparing PD-L1 for dimerization. Overall, this study casts a new light on the inhibitory mechanism of BMS inhibitors targeting PD-L1 dimerization and provides an idea for designing novel small molecule inhibitors for future cancer immunotherapy. Full article
(This article belongs to the Special Issue PD-1/PD-L1 in Cancer Immunotherapy 2022)
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12 pages, 3027 KiB  
Article
Seq2Neo: A Comprehensive Pipeline for Cancer Neoantigen Immunogenicity Prediction
by Kaixuan Diao, Jing Chen, Tao Wu, Xuan Wang, Guangshuai Wang, Xiaoqin Sun, Xiangyu Zhao, Chenxu Wu, Jinyu Wang, Huizi Yao, Casimiro Gerarduzzi and Xue-Song Liu
Int. J. Mol. Sci. 2022, 23(19), 11624; https://doi.org/10.3390/ijms231911624 - 1 Oct 2022
Cited by 13 | Viewed by 4310
Abstract
Neoantigens derived from somatic DNA alterations are ideal cancer-specific targets. In recent years, the combination therapy of PD-1/PD-L1 blockers and neoantigen vaccines has shown clinical efficacy in original PD-1/PD-L1 blocker non-responders. However, not all somatic DNA mutations result in immunogenicity among cancer cells [...] Read more.
Neoantigens derived from somatic DNA alterations are ideal cancer-specific targets. In recent years, the combination therapy of PD-1/PD-L1 blockers and neoantigen vaccines has shown clinical efficacy in original PD-1/PD-L1 blocker non-responders. However, not all somatic DNA mutations result in immunogenicity among cancer cells and efficient tools to predict the immunogenicity of neoepitopes are still urgently needed. Here, we present the Seq2Neo pipeline, which provides a one-stop solution for neoepitope feature prediction using raw sequencing data. Neoantigens derived from different types of genome DNA alterations, including point mutations, insertion deletions and gene fusions, are all supported. Importantly, a convolutional neural network (CNN)-based model was trained to predict the immunogenicity of neoepitopes and this model showed an improved performance compared to the currently available tools in immunogenicity prediction using independent datasets. We anticipate that the Seq2Neo pipeline could become a useful tool in the prediction of neoantigen immunogenicity and cancer immunotherapy. Seq2Neo is open-source software under an academic free license (AFL) v3.0 and is freely available at Github. Full article
(This article belongs to the Special Issue PD-1/PD-L1 in Cancer Immunotherapy 2022)
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Review

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13 pages, 785 KiB  
Review
PD-L1, a Potential Immunomodulator Linking Immunology and Orthodontically Induced Inflammatory Root Resorption (OIIRR): Friend or Foe?
by Jiawen Yong, Sabine Gröger, Julia von Bremen, Joerg Meyle and Sabine Ruf
Int. J. Mol. Sci. 2022, 23(19), 11405; https://doi.org/10.3390/ijms231911405 - 27 Sep 2022
Cited by 3 | Viewed by 3380
Abstract
Orthodontically induced inflammatory root resorption (OIIRR) is considered an undesired and inevitable complication induced by orthodontic forces. This inflammatory mechanism is regulated by immune cells that precede orthodontic tooth movement (OTM) and can influence the severity of OIIRR. The process of OIIRR is [...] Read more.
Orthodontically induced inflammatory root resorption (OIIRR) is considered an undesired and inevitable complication induced by orthodontic forces. This inflammatory mechanism is regulated by immune cells that precede orthodontic tooth movement (OTM) and can influence the severity of OIIRR. The process of OIIRR is based on an immune response. On some occasions, the immune system attacks the dentition by inflammatory processes during orthodontic treatment. Studies on the involvement of the PD-1/PD-L1 immune checkpoint have demonstrated its role in evading immune responses, aiming to identify possible novel therapeutic approaches for periodontitis. In the field of orthodontics, the important question arises of whether PD-L1 has a role in the development of OIIRR to amplify the amount of resorption. We hypothesize that blocking of the PD-L1 immune checkpoint could be a suitable procedure to reduce the process of OIIRR during orthodontic tooth movement. This review attempts to shed light on the regulation of immune mechanisms and inflammatory responses that could influence the pathogenesis of OIIRR and to acquire knowledge about the role of PD-L1 in the immunomodulation involved in OIIRR. Possible clinical outcomes will be discussed in relation to PD-L1 expression and immunologic changes throughout the resorption process. Full article
(This article belongs to the Special Issue PD-1/PD-L1 in Cancer Immunotherapy 2022)
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