Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently

Singh, Rakesh K.; Kim, Kyukwang; Rowswell-Turner, Rachael B.; Hansen, Jeanne N.; Khazan, Negar; Jones, Aaron M.; Sivagnanalingam, Umayal; Teramoto, Yuki; Goto, T.; Ye, Jian; Battaglia, Nicholas; Conley, Thomas; Hovanesian, Virginia; Yano, Naohiro; Pandita, Ravina; Arnold, Leggy A.; Hopson, Russel; Ojha, Debasmita; Sharon, Ashoke; Ashton, John M.; Miyamoto, Hiroshi; Schor, Nina F.; Milano, Michael T.; Linehan, David C.; Gerber, Scott A.; Moore, Richard G.

doi:10.1101/2020.08.16.252940

Cited by 3 publications

(4 citation statements)

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“…Antagonist of VDR reduced PD-L1 expression on many cancer cells lines including lung. Also, suppressed inflammatory monocytes and increased intra-tumoral CD69 + PD1 + CD8 + T cells [18]. This may explain the role of vitamin D in cancer by binding with VDR so, may prevent binding of VDR with PDL-1.…”

Section: Discussionmentioning

confidence: 94%

“…Low levels of vitamin D is recognized as a consequence of chronic inflammation rather than the cause [33]. Calcitriol treatment transcriptionally upregulated PDL-1 gene and protein expression in cancer cells, and that VDR is overexpressed in malignant tissues of pancreatic, ovarian, and lung cancer compared to normal controls and was correlated with poor prognosis [18]. Yu et al ensured that PDL-1 expression has emerged as a biomarker that predicts which patients are more likely to respond to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…It was demonstrated a differential expression of VDR (nuclear/cytoplasm) in progression of normal to invasive squamous cell carcinoma. Vitamin D receptor (VDR) mRNA is enriched in malignant lung, ovarian, and pancreatic tissues and showed poor prognoses [18].…”

Section: Introductionmentioning

confidence: 99%

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Gene expression of programmed cell death ligand-1 (PDL-1) and vitamin D receptor (VDR) with the serum vitamin D3 in lung cancer

et al. 2022

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Background Lung cancer (LC) is one of the leading causes of death worldwide. Programmed cell death receptor 1 (PD-1) interacts with its ligand (PDL-1) on T cells inhibiting its functioning which may affect the patient's immunological response. Aim Investigate if there is a link between smoking and tissue expression of PDL-1 and vitamin D receptor (VDR) in lung cancer patients. In addition, the relation of vitamin D with smoking and these biochemical markers. Methods PDL-1 and VDR expressions were evaluated by real-time PCR in 54 lung cancer biopsy samples and 36 controls to prove this hypothesis. Vitamin D levels in the blood were measured using an ELISA. Results Expressions of PDL-1 were significantly upregulated in LC patients than in controls. The highest expression was in stage II and in squamous cell carcinoma followed by small cell carcinoma then adenocarcinoma. However, VDR expressions and vitamin D levels in serum were significantly downregulating in LC patients than in controls. There was a positive correlation between PDL-1expression and duration of smoking but not smoking index. Also, there is an inverse correlation between duration of smoking, smoking index, and VDR. Conclusion Expression of PDL-1 in LC was significantly upregulated and correlated with staging. Interestingly, our current study for the first time explained the role of duration of smoking on PDL-1 and VDR in the pathogenesis of LC. As PDL-1 expression increased with duration of smoking whereas VDR decreased, this novel findings may provide a possible link between the cumulative effect of smoking and the level of expressions of these biomarkers.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Gene expression of programmed cell death ligand-1 (PDL-1) and vitamin D receptor (VDR) with the serum vitamin D3 in lung cancer

et al. 2022

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“…Currently, vitamin D is being extensively examined as a promising tool in cancer immunotherapy when administered concomitantly with checkpoint inhibitors, 15 as the induced PD‐L1 due to vitamin D positively correlate with the response to immune checkpoint inhibitors 16 . It was also shown that dual blockade of C‐X‐C motif ligand 12 (CXCL12) and PD‐1‐PD‐L1 synergistically increases an effective immune response.…”

Section: Introductionmentioning

confidence: 99%

The immunoregulatory axis (programmed death‐1/programmed death ligand‐1) on CD4+ T cells in lupus nephritis: association with vitamin D and chemokine C‐X‐C motif ligand 12

Youssry

Hussein

Moaaz

2021

Microbiology and Immunology

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Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Multiple immunomodulatory mechanisms contribute to the pathogenesis of LN. A deep understanding of the immunopathogenesis of LN is essential to identify optimal molecular targets, as most immunotherapeutic algorithms are still based on unselective drugs. The study aimed to elucidate the possible association of vitamin D deficiency with the programmed death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) axis and inflammatory response in patients with LN, as well as the relationship between the PD‐1/PD‐L1 axis and chemokine C‐X‐C motif ligand 12 (CXCL12). Flow cytometry was used to determine the frequencies of CD279 (PD‐1) and CD274 (PD‐L1) in the peripheral CD3+CD4+ cell population of persons with LN. Furthermore, ELISA was used to detect serum CXCL12 and vitamin D concentrations. A distinct decrease of PD‐1 and a significant increase of PD‐L1 was demonstrated in patients with LN compared with either SLE patients with no LN or healthy controls. The PD‐1/PD‐L1 axis was negatively correlated with different disease parameters. Vitamin D deficiency and insufficiency were more prevalent in patients with LN than in controls, being significantly associated with disease activity and inversely associated with the PD‐1/PD‐L1 expression. Moreover, CXCL12 was negatively correlated with the PD‐1/PD‐L1 axis and vitamin D concentration. The findings suggest an involvement of the PD‐1/PD‐L1 axis in lupus nephritis, which might serve as a potential highly selective therapeutic target that is more effective but less toxic. In addition, restoring adequate vitamin D levels in lupus nephritis could be a possible simple measure to control inflammatory immune responses.

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Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma

Shi,

Ge,

Cai

et al. 2023

Front. Immunol.

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IntroductionLow-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. MethodsWe conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis.ResultsOur findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR.DiscussionThese findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

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Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently

Cited by 3 publications

References 37 publications

Gene expression of programmed cell death ligand-1 (PDL-1) and vitamin D receptor (VDR) with the serum vitamin D3 in lung cancer

Gene expression of programmed cell death ligand-1 (PDL-1) and vitamin D receptor (VDR) with the serum vitamin D3 in lung cancer

The immunoregulatory axis (programmed death‐1/programmed death ligand‐1) on CD4+ T cells in lupus nephritis: association with vitamin D and chemokine C‐X‐C motif ligand 12

Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma

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