The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

Hou, Bo; Chen, Ting; Zhang, He; Li, Jiatong; Shang, Guanning

doi:10.3389/fimmu.2023.1123244

Cited by 25 publications

(13 citation statements)

References 121 publications

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“…When multiple lysines of the target protein are simultaneously tagged by a single ubiquitin molecule, it is referred to as polyubiquitination [ 287 ]. PD-L1 expression is highly regulated by ubiquitin-proteasome systems (UPS), such as STUB1 and SPOP, promoting PD-L1 polyubiquitination and degradation, while CSN5 and the deubiquitinating enzyme DUB antagonize its degradation [ 288 ].…”

Section: Ubiquitination Modification Of Pd-l1 Proteinmentioning

confidence: 99%

Regulatory mechanisms of PD-1/PD-L1 in cancers

Lin,

Kang,

Chen

et al. 2024

Mol Cancer

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Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.

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Section: Ubiquitination Modification Of Pd-l1 Proteinmentioning

confidence: 99%

Regulatory mechanisms of PD-1/PD-L1 in cancers

Lin,

Kang,

Chen

et al. 2024

Mol Cancer

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“…PD-1/PD-L1 modification participated in governing immune escape and affecting cancer immunotherapy ( 98 ). Moreover, the E3 ubiquitin ligases improved tumor immunotherapy via controlling PD-1/PD-L1 protein accumulation in tumor microenvironment ( 99 ). In the following paragraphs, we will describe the role of PTMs in regulation of PD-1 and PD-L1 ( Tables 1 , 2 ).…”

Section: Pd-1 and Pd-l1 Are Regulated By Ptmsmentioning

confidence: 99%

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Ren,

Wang,

Liu

et al. 2024

Front. Immunol.

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Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

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“…Inhibitory immune checkpoint molecules include programmed cell death ligand (PD-1), programmed death ligand (PD-L1), PD-L2, B7-H3 (CD276), B7-H4 (VTCN1), LAG3, TIM-3, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) ( 18 , 19 ). Although immunotherapy has improved the survival of certain cancer patients, primary resistance and acquired resistance in immunotherapy attenuate the cancer treatment outcomes ( 20 , 21 ). Hence, it is pivotal to uncover the mechanism of immunotherapy resistance and to develop the compounds that improve immunotherapy.…”

Section: Role Of Hdac In Immunotherapymentioning

confidence: 99%

Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer

Chen²,

Shen³

2023

Front. Immunol.

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Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs via mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.

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The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy

Cited by 25 publications

References 121 publications

Regulatory mechanisms of PD-1/PD-L1 in cancers

Regulatory mechanisms of PD-1/PD-L1 in cancers

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer

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