Upregulation of PD-L1 in Senescence and Aging

Onorati, Angelique; Havas, Aaron; Lin, Brian M.; Rajagopal, Jayaraj; Adams, Peter; Dou, Zhixun

doi:10.1128/mcb.00171-22

Cited by 60 publications

(45 citation statements)

References 78 publications

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“…The inflammatory cytokines released by senescent cells can upregulate PD-L1 in non-senescent cells via the JAK-STAT pathway [ 161 ]. This suggests that the SASP can confer an immune checkpoint response in non-senescent cells.…”

Section: Discussionmentioning

confidence: 99%

The Potential of Senescence as a Target for Developing Anticancer Therapy

Shim

Jeoung

2023

IJMS

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Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.

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Section: Discussionmentioning

confidence: 99%

The Potential of Senescence as a Target for Developing Anticancer Therapy

Shim

Jeoung

2023

IJMS

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“…Cellular senescence and aging are associated with PD-L1 upregulation, and a large variety of proinflammatory cytokines, chemokines, growth factors, and proteases secreted by senescent cells upregulate PD-L1 expression in non-senescent control cells via the JAK-STAT pathway [ 30 ]. However, the median age of the treatment success group was higher than that of the treatment failure group in our study.…”

Section: Discussionmentioning

confidence: 99%

Dynamics in the expression of programmed death ligand 1 and cluster of differentiation 163 in the tumor microenvironment of uterine cervical cancer: a single-center retrospective study

et al. 2023

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Background Radiotherapy (RT) destroys cancer cells and activates the immune system while suppressing the immunity of tumor-associated tissues, including the tumor microenvironment (TME). However, to date, no anti-tumor therapeutic strategy that uses these immune mechanisms has been established. This study investigated changes in the immunity of the TME during standard radical RT for cervical cancer combined with external beam RT and brachytherapy and determined whether these changes affect prognosis. Methods Twenty-six patients who had completed radical RT for cervical cancer were categorized into the following two groups according to whether the cancer recurred and/or metastasized within 2 years after the start of treatment: treatment failure (n = 14) and treatment success (n = 12). We assessed the expression of programmed death 1, programmed death ligand 1 (PD-L1), cluster of differentiation (CD) 8, CD68, CD163, Forkhead box protein P3, and hypoxia-inducible factor-1α in the TME of cervical tissues collected periodically during treatment and evaluated the difference in expression rates of each marker between the success and failure groups and assessed its effect on prognosis. Results The expression levels of PD-L1 and CD163 in the TME in the treatment success group were lower than those in the treatment failure group at the midpoint during brachytherapy (p < 0.01 and p = 0.08, respectively), and the 2-year progression-free-survival (PFS) rate depended on the expression levels of PD-L1 and CD163 (p = 0.04 and p = 0.02, respectively). Conclusions The expression rates of CD163 and PD-L1 in the TME during brachytherapy were related to treatment response and the 2-year PFS. This study may increase our understanding of tumor-associated immunity in the TME and aid in the development of therapies targeting PD-L1 or M2 macrophages in the TME in conjunction with RT, especially brachytherapy, for cervical cancer patients.

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“…Multiple mechanisms regulate PD-L1 at the transcriptional, posttranscriptional, and posttranslational levels ( 22 ). The pro-inflammatory secretome of senescent cells upregulates PD-L1 mRNA level through the JAK-STAT pathway ( 23 ). In cancer cells , cyclin D-CDK4/6 dependent phosphorylation of SPOP/Cullin-3 ubiquitin ligase complex destabilizes PD-L1 via proteasome-mediated degradation, but inhibition of CDK4/6 significantly elevates PD-L1 level ( 24 ).…”

Section: P16-mediated Inhibition Of Cdk4/6 Stabilizes Pd-l1 In Cellul...mentioning

confidence: 99%

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

Majewska

Agrawal

Mayo

et al. 2023

Preprint

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The accumulation of senescent cells promotes aging, but the molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.

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Upregulation of PD-L1 in Senescence and Aging

Abstract: Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis.

Cited by 60 publications

References 78 publications

The Potential of Senescence as a Target for Developing Anticancer Therapy

The Potential of Senescence as a Target for Developing Anticancer Therapy

Dynamics in the expression of programmed death ligand 1 and cluster of differentiation 163 in the tumor microenvironment of uterine cervical cancer: a single-center retrospective study

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

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