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Cited by 681Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

The DOI matches its Crossref record; 153 of the 153 references it cites were found in a registry or an index.

Regulation of PD-L1 expression in the tumor microenvironment

Open access
Yi, Ming, Niu, Mengke, Xu, Linping, Luo, Suxia, Wu, Kongming·2021·Journal of Hematology & Oncology
DOI 10.1186/s13045-020-01027-5PMC PMC7792099
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Abstract

Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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Fig. 1 The regulators of PD-L1 expression. PD-L1 abundance is regulated by genomic alterations (amplification or translocation), epigenetic modifications (methylation of histone or CpG island, and histone acetylation), transcriptional regulation (inflammatory stimuli and oncogenic signals), post-transcriptional regulation (miRNA, the status of 3′- UTR, RAS, and Angiotensin II), and post-translational modification (ubiquitination, phosphorylation, glycosylation, palmitoylation). H3K4me3: tri-methylation of histone H3 on lysine 4; H3K27me3: tri-methylation of histone H3 on lysine 27; EGFR: epidermal growth factor receptor; IRF: interferon-responsive factor; IFN: interferon; DSB: double-strand break; GSK3β: glycogen synthase kinase 3β; PI3K: phosphoinositide 3-kinase; NF-κB: Nuclear factor kappa-B; HIF-1α: hypoxia-inducible factor-1α; ALK: Anaplastic lymphoma kinase; ER: endoplasmic reticulum
Fig. 1 The regulators of PD-L1 expression. PD-L1 abundance is regulated by genomic alterations (amplification or translocation), epigenetic modifications (methylation of histone or CpG island, and histone acetylation), transcriptional regulation (inflammatory stimuli and oncogenic signals), post-transcriptional regulation (miRNA, the status of 3′- UTR, RAS, and Angiotensin II), and post-translational modification (ubiquitination, phosphorylation, glycosylation, palmitoylation). H3K4me3: tri-methylation of histone H3 on lysine 4; H3K27me3: tri-methylation of histone H3 on lysine 27; EGFR: epidermal growth factor receptor; IRF: interferon-responsive factor; IFN: interferon; DSB: double-strand break; GSK3β: glycogen synthase kinase 3β; PI3K: phosphoinositide 3-kinase; NF-κB: Nuclear factor kappa-B; HIF-1α: hypoxia-inducible factor-1α; ALK: Anaplastic lymphoma kinase; ER: endoplasmic reticulumCC BY · PubMed Central
Fig. 2 The current immune checkpoint inhibitor therapy could be further enhanced by regulating PD-L1 expression. Agents regulating PD-L1 expression might have a synergistic effect with the current immune checkpoint inhibitors. For example, targeting therapies such as CDK4/6 inhibitor upregulated PD-L1 expression and promoted immune escape. This treatment-induced immune evasion could be overcome by combination therapies containing α-PD-1/PD-L1 (the left panel). Besides, adjuvant treatment regulating PD-L1 expression might elevate the sensitivity to α-PD-1/PD-L1 or other immune checkpoint inhibitors. For instance, metformin downregulated PD-L1 by promoting endoplasmic-reticulum-associated degradation, and the combination therapy of metformin and α-CTLA-4 had a synergistic antitumor activity (the right panel). CDK: cyclin-dependent kinase; CTLA-4: cytotoxic T Lymphocyte antigen 4; ER: endoplasmic reticulum
Fig. 2 The current immune checkpoint inhibitor therapy could be further enhanced by regulating PD-L1 expression. Agents regulating PD-L1 expression might have a synergistic effect with the current immune checkpoint inhibitors. For example, targeting therapies such as CDK4/6 inhibitor upregulated PD-L1 expression and promoted immune escape. This treatment-induced immune evasion could be overcome by combination therapies containing α-PD-1/PD-L1 (the left panel). Besides, adjuvant treatment regulating PD-L1 expression might elevate the sensitivity to α-PD-1/PD-L1 or other immune checkpoint inhibitors. For instance, metformin downregulated PD-L1 by promoting endoplasmic-reticulum-associated degradation, and the combination therapy of metformin and α-CTLA-4 had a synergistic antitumor activity (the right panel). CDK: cyclin-dependent kinase; CTLA-4: cytotoxic T Lymphocyte antigen 4; ER: endoplasmic reticulumCC BY · PubMed Central

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Metadata

Authors
Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K.
Affiliations
  • Tongji Hospital (CN)
  • Zhengzhou University (CN)
Corresponding author
  • Luo, Suxia
  • Wu, Kongming
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2021-01-07
Volume
14
Issue
1
Pages
10-10
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-020-01027-5
PMC
PMC7792099
OpenAlex
W3118950316
Cited by
681
References
153
Citations by year
2026: 114 · 2025: 108 · 2024: 169 · 2023: 130 · 2022: 113 · 2021: 47
FWCI
13.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81874120, 82073370)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
PD-L1, PD-1/PD-L1 axis, tumor microenvironment, tumor immune evasion, transcriptional regulation, post-transcriptional regulation, post-translational regulation, T cell exhaustion, immune checkpoint inhibitors, predictive biomarkers
MeSH terms
Animals, Humans, Neoplasms, Protein Processing, Post-Translational, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Tumor Escape, Epigenesis, Genetic, Tumor Microenvironment, B7-H1 Antigen

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