Increased PD-L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation.
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ABSTRACT:
SUBMITTER: Dickinson SE
PROVIDER: S-EPMC8277687 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:At present, targeting PD-1/PD-L1 axis for immune checkpoint inhibition has improved treatment of various tumor entities, including head and neck squamous cell carcinoma (HNSCC). However, one part of the patient cohort still shows little improvement or even hyperprogression. We established three radioresistant (RR) and three radiosensitive (RS) HNSCC cell lines. RR cells showed prolonged survival as well as delayed and diminished apoptosis after irradiation with vimentin expression but no E-cadherin expression, whereas RS cell lines died early and exhibited early apoptosis after irradiation and high vimentin expression. Here, we present results demonstrating differential basal PD-L1 gene and protein expression in RR and RS HNSCC cell lines. Moreover, we observed a radiation dose dependent increase of total PD-L1 protein expression in RR cell lines up to 96h after irradiation compared to non-irradiated (non-IRR) cells. We found a significant GSK-3beta phosphorylation, resulting in an inactivation, after irradiation of RR cell lines. Co-immunoprecipitation experiments revealed decreased interaction of GSK-3beta with PD-L1 in non-IRR compared to irradiated (IRR) RR cells leading to PD-L1 stabilization in RR cells. PD-L1 knockdown in RR cells showed a strong decrease in cell survival. In summary, our results suggest an irradiation dependent increase in basal PD-L1 expression in RR HNSCC cell lines via GSK-3beta inactivation.
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Project description:ObjectivesLaryngotracheal stenosis (LTS) is a fibrotic condition of the upper airway. Recent evidence suggests dysregulated host immunity plays a role in LTS development and progression. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, targeted by paradigm-shifting immunotherapies for cancer treatment, has also recently been implicated in the pathogenesis of fibrotic pulmonary disease. However, a role for the PD-1/PD-L1 axis in the proximal airway fibrosis seen in LTS patients has not been explored.Study designControlled ex vivo study.MethodsExpression of PD-1, PD-L1, CD4, and CD8 were evaluated using immunohistochemical staining of cricotracheal resection specimens from postintubation iatrogenic laryngotracheal stenosis (iLTS), idiopathic subglottic stenosis (iSGS) patients, and normal controls derived from rapid autopsy (n = 8 per group). Fibroblasts derived from iLTS scar were also treated with transforming growth factor beta 1 (TGFβ1) and analyzed for PD-L1 expression by quantitative real-time polymerase chain reaction (n = 6).ResultsiLTS specimens exhibited increased expression of PD-1, PD-L1, and CD4 (all P < .0167) compared to controls, whereas iSGS specimens exhibited increased expression of PD-1 and CD4 (P < .0167) compared to controls. PD-1, PD-L1, and CD4 showed periepithelial patterns of expression in both disease cohorts. TGFβ1 treatment of iLTS fibroblasts increased expression of PD-L1 (the cognate ligand for PD-1).ConclusionExpression of both PD-1 and its ligand PD-L1 are significantly greater in patients with iLTS compared to controls, and PD-1 expression is also elevated in patients with iSGS. Given published evidence implicating the PD-1/PD-L1 axis in pulmonary fibrosis, this suggests a possible role for checkpoint inhibitors targeting the PD-1/PD-L1 axis for the treatment of LTS.Level of evidenceN/A Laryngoscope, 131:967-974, 2021.
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Project description:Halloysite clay nanotubes (HNTs) have been proposed as highly biocompatible for several biomedical applications. Various polymers have been used to functionalize HNTs, but scarce information exists about polystyrene for this purpose. This work evaluated polystyrene-functionalized HNTs (FHNTs) by comparing its effects with non-FHNTs and innocuous talc powder on in vitro and in vivo models. Monocyte-derived human or murine macrophages and the RAW 264.7 cell line were treated with 0.01, 0.1, 1, and 100 μg mL-1 FHNTs, HNTs, or talc to evaluate the cytotoxic and cytokine response. Our results show that nanoclays did not cause cytotoxic damage to macrophages. Only the 100 μg mL-1 concentration induced slight proinflammatory cytokine production at short exposure, followed by an anti-inflammatory response that increases over time. CD1 mice treated with a single dose of 1, 2.5, or 5 mg Kg-1 of FHNTs or HNTs by oral and inhalation routes caused aluminum accumulation in the kidneys and lungs, without bodily signs of distress or histopathological changes in any treated mice, evaluated at 48 h and 30 days post-treatment. Nanoclay administration simultaneously by four different parenteral routes (20 mg Kg-1) or the combination of administration routes (parenteral + oral or parenteral + inhalation; 25 mg Kg-1) showed accumulation on the injection site and slight surrounding inflammation 30 days post-treatment. CD1 mice chronically exposed to HNTs or FHNTs in the bedding material (ca 1 mg) throughout the parental generation and two successive inbred generations for 8 months did not cause any inflammatory process or damage to the abdominal organs and the reproductive system of the mice of any of the generations, did not affect the number of newborn mice and their survival, and did not induce congenital malformations in the offspring. FHNTs showed a slightly less effect than HNTs in all experiments, suggesting that functionalization makes them less cytotoxic. Doses of up to 25 mg Kg-1 by different administration routes and permanent exposure to 1 mg of HNTs or FHNTs for 8 months seem safe for CD1 mice. Our in vivo and in vitro results indicate that nanoclays are highly biocompatible, supporting their possible safe use for future biomedical and general-purpose applications.
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Project description:The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down-regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation.
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Project description:Programmed death-ligand 1 (PD-L1), expressed on the surface of tumor cells, can bind to programmed cell death-1 (PD-1) on T cells. The interaction of PD-1 and PD-L1 can inhibit T-cell responses by decreasing T-cell activity and accelerating their apoptosis. Various cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T-cell immunity, and immunotherapies targeting the PD-1/PD-L1 axis have been shown to exert remarkable anti-tumor effects; however, not all tumor patients benefit from these therapies. Therefore, study of the mechanisms regulating PD-L1 expression are imperative. In this review, we explore regulation of PD-L1 expression in the contexts of gene transcription, signaling pathways, histone modification and remodeling, microRNAs, long noncoding RNAs, and post-translational modification. Current developments in studies of agents that block PD-L1 and correlations between immunotherapies targeting PD-1/PD-L1 and PD-L1 expression are also summarized. Our review will assist in understanding of PD-L1 expression regulation and discusses the implications of reported findings in cancer diagnosis and immunotherapy.
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Project description:PurposeSubsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas.MethodsPD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry.ResultsPituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes.ConclusionsHuman pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.
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Project description:There are no effective medical treatments for WHO grade III (anaplastic) meningioma. Patients with this high-grade malignancy have a median survival of less than two years. Therapeutics that modulate the mechanisms that inhibit local immune responses in the tumor microenvironment are showing significant and durable clinical responses in patients with treatment refractory high-grade tumors. We examined the immune infiltrate of 291 meningiomas including WHO grade I-III meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In anaplastic meningioma, there is a sharp decrease in the number of T cells, including the numbers of CD4+ and CD8+ T cells and cells expressing PD-1 and there is also an increase in the number of FOXP3 expressing immunoregulatory (Treg) cells. PD-L1 expression is increased in anaplastic meningioma - both mRNA and protein. Using patient derived meningioma cell, we confirm that PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. This work indicates that high-grade meningioma harbor an immunosuppressive tumor microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the aggressive phenotype of these tumors.
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Project description:Dermal macrophages containing melanin increase skin pigmentation since dermal melanin removal is slower than epidermal melanin removal. Lymphatic vessels are also involved in melanin clearance. We evaluated whether radiofrequency (RF) irradiation induced an increase in HSP90, which promotes lymphangiogenesis by activating the BRAF/MEK/ERK pathway and decreasing tyrosinase activity, in the UV-B exposed animal model. The HSP90/BRAF/MEK/ERK pathway was upregulated by RF. Tyrosinase activity and the VEGF-C/VEGFR 3/PI3K/pAKT1/2/pERK1/2 pathway, which increase lymphangiogenesis, as well as the expression of the lymphatic endothelial marker LYVE-1, were increased by RF. Additionally, the number of melanin-containing dermal macrophages, the melanin content in the lymph nodes, and melanin deposition in the skin were decreased by RF. In conclusion, RF increased HSP90/BRAF/MEK/ERK expression, which decreased tyrosinase activity and increased lymphangiogenesis to eventually promote the clearance of dermal melanin-containing macrophages, thereby decreasing skin pigmentation.
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Project description:BackgroundTumor cells express programmed death ligand 1 (PD-L1) and is a key immune evasion mechanism. PD-L1 expression in multiple breast cancer cell lines was evaluated to identify intrinsic differences that affect their potential for immune evasion.MethodsPD-L1 expression was analyzed in six breast cancer cell lines: AU565&MCF7 (luminal), BT20&HCC1143 (basal A), MDA231&HCC38 (basal B). Surface and intracellular PD-L1 expression +/- interferon γ for 48 hours was measured by flow cytometry. PD-L1 gene expression data for all breast cancer cell lines in the Comprehensive Cell Line Encyclopedia (CCLE) was analyzed. Correlation between PD-L1 levels and clinicopathologic parameters was analyzed within Oncomine datasets. A tissue microarray containing 61 invasive breast cancer primary tumor cores was stained for PD-L1 expression and analyzed.ResultsBasal breast cancer cells constitutively express the highest levels of PD-L1. All cell lines increased PD-L1 expression with interferon γ, but basal B cells (MDA-231 and HCC38) demonstrated the largest increases. There were no differences in protein localization between cell lines. In the CCLE data, basal cell lines demonstrated higher mean PD-L1 expression compared to luminal cell lines. High PD-L1 expressing basal cell lines over-express genes involved in invasion, proliferation, and chemoresistance compared to low PD-L1 basal cell lines. High PD-L1 basal cell lines had lower expression of IRF2BP2 and higher STAT1 levels compared to low PD-L1 expressing cell lines. Within Oncomine datasets PDL1 mRNA levels were higher in basal type tumors. The TMA analysis demonstrated that lymph node positive cases had higher levels of PD-L1 protein expression compared to lymph node negative cases.ConclusionsBasal type breast cancer (especially basal B) express greater levels of PD-L1 constitutively and with IFN γ. High PD-L1 basal cells over-express genes involved in invasion, motility, and chemoresistance. Targeting PD-L1 may enhance eradication of aggressive breast cancer cells by the immune system.
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Project description:BackgroundThe ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR+/ALK+ non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful.MethodsThe correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models.ResultsPositive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression.ConclusionsHGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.
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