Increased PD‐L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation

Dickinson, Sally E.; Khawam, Maria; Kirschnerova, Viktoria; Vaishampayan, Prajakta; Centuori, Sara; Saboda, Kathylynn; Calvert, Valerie; Petricoin, Emanuel F.; Curiel‐Lewandrowski, Clara

doi:10.1111/php.13406

Cited by 11 publications

(25 citation statements)

References 28 publications

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“…However, the UVB light source used in our experiments above does not accurately represent the distribution of solar UV wavelengths that humans and other terrestrial organisms are routinely exposed to. We therefore repeated our cell survival assays using a solar simulated light (SSL) source that is composed of approximately 93% UVA and 7% UVB (29). Interestingly, as shown in Figure 5a , pre-treatment of HaCaT cells with NOB for 24 hr failed to protect the cells from SSL and instead greatly sensitized the cells to the anti-proliferative effects of this light source.…”

Section: Resultsmentioning

confidence: 99%

“…We therefore repeated our cell survival assays using a solar simulated light (SSL) source that is composed of approximately 93% UVA and 7% UVB (29). Interestingly, as shown in Figure 5a, pre-treatment of HaCaT cells with NOB for 24 hr failed to protect the cells from SSL and instead greatly sensitized the cells to the anti-proliferative effects of this light source.…”

Section: Nobiletin Sensitizes Keratinocytes To Uva Radiationmentioning

confidence: 99%

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The flavonoid nobiletin exhibits differential effects on cell viability in keratinocytes exposed to UVA versus UVB radiation

Cvammen

Kemp

2022

Preprint

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The polymethoxylated flavonoid nobiletin has been shown to suppress inflammatory responses to UVB radiation and to enhance circadian rhythms. Because expression of the core nucleotide excision repair (NER) factor XPA and the rate of removal of UV photoproducts from DNA are regulated by the circadian clock, we investigated whether the beneficial effects of nobiletin in UVB-exposed cells could be due in part to enhanced DNA repair. Though nobiletin limited UVB-irradiated human keratinocytes from undergoing cell death, we found that this enhanced survival was not associated with increased NER or XPA expression. Instead, nobiletin reduced initial UV photoproduct formation and promoted a G1 cell cycle arrest. We then examined the implications of this findings for exposures to solar radiation through use of a solar simulated light (SSL) source that contains primarily UVA radiation. In striking contrast to the results obtained with UVB radiation, nobiletin instead sensitized keratinocytes to both the SSL and a more defined UVA light source. This enhanced cell death was correlated with a photochemical change in nobiletin absorption spectrum in the UVA range. We conclude that nobiletin is unlikely to be a useful compound for protecting keratinocytes against the harmful effects of solar UV radiation.

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Section: Resultsmentioning

confidence: 99%

Section: Nobiletin Sensitizes Keratinocytes To Uva Radiationmentioning

confidence: 99%

The flavonoid nobiletin exhibits differential effects on cell viability in keratinocytes exposed to UVA versus UVB radiation

Cvammen

Kemp

2022

Preprint

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“…[27][28][29] Notably, PD-L1 expression in normal human skin is inducible by acute exposure to ultraviolet light, a trend that is reproducible in SKH-1 hairless immunocompetent mice and in cell culture. 27 The PD-L1 gene promoter contains binding elements for several stress-response transcription factors, including signal transducer and activator of transcription 1 (STAT1), STAT3, nuclear factor-κB, and hypoxiainducible factor 1/3. 30 Thus, PD-L1 may aid in the epidermal response to damaging stimuli via upregulation of transcription and resultant protein expression in keratinocytes, contributing to dampening of the immune response in the skin.…”

Section: Pd-l1 In Normal Skin and Actinic Keratosesmentioning

confidence: 94%

“…Only a few studies have included normal epidermis and actinic keratoses in their analysis of human PD‐L1 expression in the skin. Normal human epidermis exhibits low baseline expression of PD‐L1, and variable levels have been reported in AKs 27–29 . Notably, PD‐L1 expression in normal human skin is inducible by acute exposure to ultraviolet light, a trend that is reproducible in SKH‐1 hairless immunocompetent mice and in cell culture 27 .…”

Section: Pd‐l1 In Normal Skin and Actinic Keratosesmentioning

confidence: 96%

“…Normal human epidermis exhibits low baseline expression of PD‐L1, and variable levels have been reported in AKs 27–29 . Notably, PD‐L1 expression in normal human skin is inducible by acute exposure to ultraviolet light, a trend that is reproducible in SKH‐1 hairless immunocompetent mice and in cell culture 27 . The PD‐L1 gene promoter contains binding elements for several stress‐response transcription factors, including signal transducer and activator of transcription 1 (STAT1), STAT3, nuclear factor‐κB, and hypoxia‐inducible factor 1/3 30 .…”

Section: Pd‐l1 In Normal Skin and Actinic Keratosesmentioning

confidence: 96%

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Review: PD‐L1 as an emerging target in the treatment and prevention of keratinocytic skin cancer

Vaishampayan

Curiel‐Lewandrowski

Dickinson

2022

Molecular Carcinogenesis

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Recent advances in the understanding and targeting of immune checkpoints have led to great progress in immune therapies against many forms of cancer. While many types of immune checkpoints are currently targeted in the clinic, this review will focus on recent research implicating the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis as an emerging focus for the treatment of keratinocytic tumors. PD-L1 is of particular interest in nonmelanoma skin cancer (NMSC), as it is not only upregulated in these tumors but is stimulated by environmental ultraviolet exposure. This response may also make PD-L1 an excellent target for photochemoprevention using topically applied small molecule inhibitors.Here, we summarize recent investigations on PD-L1 expression and clinically relevant immune checkpoint inhibitor treatment in cutaneous squamous cell carcinoma, basal cell carcinoma, and head and neck squamous cell carcinoma, as well as small molecule agents targeting PD-L1 that may be useful for clinical development aiming at treatment or prevention of NMSC.

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The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Salminen

2024

J Mol Med

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The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. Key messages Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

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Increased PD‐L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation

Cited by 11 publications

References 28 publications

The flavonoid nobiletin exhibits differential effects on cell viability in keratinocytes exposed to UVA versus UVB radiation

The flavonoid nobiletin exhibits differential effects on cell viability in keratinocytes exposed to UVA versus UVB radiation

Review: PD‐L1 as an emerging target in the treatment and prevention of keratinocytic skin cancer

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

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