Morphine-3-glucuronide upregulates PD-L1 expression &lt;i&gt;via&lt;/i&gt; TLR4 and promotes the immune escape of non-small cell lung cancer

Wang, Kaiyuan; Wang, Jian; Liu, Ting; Yu, Wenwen; Dong, Nan; Zhang, Chen; Xia, Wenbin; Wei, Feng; Yang, Lili; Ren, Xiubao

doi:10.20892/j.issn.2095-3941.2020.0442

Cited by 24 publications

(14 citation statements)

References 37 publications

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“…Several studies have shown that IFN-γ can induce PD-L1 expression through the IFN-γ/JAK/STAT1 signaling pathway, thereby promoting the immune escape of cancer cells [ 101 , 102 ]. In addition to IFN-γ, several other inflammatory cytokines also enhance PD-L1 expression on cancer cells or tumor-associated stromal cells, such as IFN-α/β [ 66 ], Toll-like receptors3/4 [ 63 , 73 ], TNF-α [ 103 ], TGF-β [ 104 ], and IL-4/6/10/17/27 [ 64 , 65 , 71 , 72 , 105 ]. Interestingly, the detection of the expression of inflammatory cytokines (e.g., IFN-γ, TNF-α, and several ILs) is a predictor of immune checkpoint therapy outcome for advanced NSCLC, while high expression of inflammatory cytokines is positively correlated with anti-PD-1 therapeutic effectiveness [ 106 ].…”

Section: The Role Of Pd-l1 In Tumor Immune Escapementioning

confidence: 99%

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies

et al. 2022

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Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8+ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets.

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Section: The Role Of Pd-l1 In Tumor Immune Escapementioning

confidence: 99%

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies

et al. 2022

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“…administration in rodents is abolished by administration of TLR4 antagonists, as well as in a TLR4 –/– mouse model ( Figure 2 ; Due et al, 2012 ; Allette et al, 2017 ). Consistently, M3G seems to display proinflammatory properties through upregulation of NF-κB and proinflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα), such that it was proposed to be involved in the modulation of morphine properties ( Figure 2 ; Lewis et al, 2010 ; Grace et al, 2014 ; Doyle and Murphy, 2018 ; Iqbal et al, 2020 ; Wang et al, 2021 ). These interesting findings take into account that a considerable number of studies have described the immunomodulatory effects of morphine and M3G ( Wybran et al, 1979 ; Shavit et al, 1986 ; Freier and Fuchs, 1994 ; Thomas et al, 1995 ; Wang et al, 2012 ; Eisenstein, 2019 ).…”

Section: Morphine-3-glucuronidementioning

confidence: 94%

“…This reporter cell line expresses the human TLR4 and a reporter gene under the control of a promoter inducible by NF-κB and AP-1, two transcription factors involved in TLR4 signaling cascade and proinflammatory cytokines release. In addition, it has been shown that the PI3K/AKT pathway, the third TLR4 intra-cellular signaling pathway, is also activated following M3G stimulation ( Figure 2 ; Hutchinson et al, 2010 ; Wang et al, 2021 ). In human cancer cell lines, the activation of the AKT pathway by M3G results in upregulation of programmed death ligand 1 (PD-L1), which promotes tumor growth ( Wang et al, 2021 ).…”

Section: Morphine-3-glucuronidementioning

confidence: 98%

“…In addition, it has been shown that the PI3K/AKT pathway, the third TLR4 intra-cellular signaling pathway, is also activated following M3G stimulation ( Figure 2 ; Hutchinson et al, 2010 ; Wang et al, 2021 ). In human cancer cell lines, the activation of the AKT pathway by M3G results in upregulation of programmed death ligand 1 (PD-L1), which promotes tumor growth ( Wang et al, 2021 ). It is, however, worth noting that, although Wang et al (2021) observed activation of the AKT and NF-κB pathways in the A549 cell line (a human lung cancer cell line), they did not observe activation of the MAPK pathway in their model.…”

Section: Morphine-3-glucuronidementioning

confidence: 98%

“…In human cancer cell lines, the activation of the AKT pathway by M3G results in upregulation of programmed death ligand 1 (PD-L1), which promotes tumor growth ( Wang et al, 2021 ). It is, however, worth noting that, although Wang et al (2021) observed activation of the AKT and NF-κB pathways in the A549 cell line (a human lung cancer cell line), they did not observe activation of the MAPK pathway in their model.…”

Section: Morphine-3-glucuronidementioning

confidence: 99%

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Morphine-3-Glucuronide, Physiology and Behavior

Gabel

Hovhannisyan

Berkati

et al. 2022

Front. Mol. Neurosci.

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Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5′-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G’s behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia.

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