A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma

Duijn, A.V.H.M.; Willemsen, Karin J.; Uden, Nathalie O. van; Hoyng, Lieke; Erades, Sterre; Koster, Jan; Luiten, Rosalie M.; Bakker, Walbert J.

doi:10.1007/s00262-021-03007-1

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…Moreover, the present results show that PD-L1 up-regulation is counteracted by the HIF-1α inhibition, indicating that PD-L1 is the target, and it depends on HIF-1α under hypoxic conditions. It is important to underline that the present results are in agreement with previous findings [ 36 ]. Duijn et al (2021) reported a pronounced influence of hypoxia on IFNγ-induced PD-L1 mRNA expression, which is controlled by the HIF1 knockdown as well as at a 952 bp PD-L1 promoter fragment.…”

Section: Discussionsupporting

confidence: 94%

“…Duijn et al (2021) reported a pronounced influence of hypoxia on IFNγ-induced PD-L1 mRNA expression, which is controlled by the HIF1 knockdown as well as at a 952 bp PD-L1 promoter fragment. Their findings indicate a role of hypoxia on PD-L1 expression [ 36 ]. However, Ruf et al (2016) showed that in renal cell carcinoma PD-L1 is regulated by HIF-2α, not HIF-1α [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia

Yong

Gröger

Bremen

et al. 2022

Cells

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Recent studies have revealed that hypoxia alters the PD-L1 expression in periodontal cells. HIF-1α is a key regulator for PD-L1. As hypoxia presents a hallmark of an orthodontically induced microenvironment, hypoxic stimulation of PD-L1 expression may play vital roles in immunorthodontics and orthodontically induced inflammatory root resorption (OIIRR). This study aims to investigate the hypoxic regulation of PD-L1 in cementoblasts, and its interaction with hypoxia-induced HIF-1α expression. The cementoblast (OCCM-30) cells (M. Somerman, NIH, NIDCR, Bethesda, Maryland) were cultured in the presence and absence of cobalt (II) chloride (CoCl2). Protein expression of PD-L1 and HIF-1α as well as their gene expression were evaluated by Western blotting and RT-qPCR. Immunofluorescence was applied to visualize the localization of the proteins within cells. The HIF-1α inhibitor (HY-111387, MedChemExpress) was added, and CRISPR/Cas9 plasmid targeting HIF-1α was transferred for further investigation by flow cytometry analysis. Under hypoxic conditions, cementoblasts undergo an up-regulation of PD-L1 expression at protein and mRNA levels. Silencing of HIF-1α using CRISPR/Cas9 indicated a major positive correlation with HIF-1α in regulating PD-L1 expression. Taken together, these findings show the influence of hypoxia on PD-L1 expression is modulated in a HIF-1α dependent manner. The HIF-1α/PD-L1 pathway may play a role in the immune response of cementoblasts. Thus, combined HIF-1α/PD-L1 inhibition could be of possible therapeutic relevance for OIIRR prevention.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia

Yong

Gröger

Bremen

et al. 2022

Cells

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“…Immune escape from cytotoxic T cells is essential for survival and proliferation of melanoma cells. It is known that hypoxia contributes to immune escape of cancer cells including melanoma (Barsoum et al, 2014;Li et al, 2018;Liu and Curran, 2020;Van Duijn et al, 2022). The tumor nest was packed with melanoma cells in untreated melanoma, whereas melanoma treated with IDF-11774 had numerous clefts and fissures (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, tumor cell proliferation can be inhibited by anti-tumor effect of CD8-positive T cells and their activities (Mahmoud et al, 2017;Pio et al, 2019). The role of hypoxia in immune escape has been identified (Barsoum et al, 2014;Li et al, 2018;Zou et al, 2018;Liu and Curran, 2020;Tittarelli et al, 2020;Van Duijn et al, 2022). For metastasis, melanoma needs to adapt to microenvironmental changes.…”

Section: Original Articlementioning

confidence: 99%

Anti-Tumor Effect of IDF-11774, an Inhibitor of Hypoxia-Inducible Factor-1, on Melanoma

Kim

Lee

2022

Biomol Ther (Seoul)

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Melanoma is one of the most aggressive skin cancers. Hypoxia contributes to the aggressiveness of melanoma by promoting cancer growth and metastasis. Upregulation of cyclin D1 can promote uncontrolled cell proliferation in melanoma, whereas stimulation of cytotoxic T cell activity can inhibit it. Epithelial mesenchymal transition (EMT) plays a critical role in melanoma metastasis. Hypoxia-inducible factor-1α (HIF-1α) is a main transcriptional mediator that regulates many genes related to hypoxia. CoCl2 is one of the most commonly used hypoxia-mimetic chemicals in cell culture. In this study, inhibitory effects of IDF-11774, an inhibitor of HIF-1α, on melanoma growth and metastasis were examined using cultured B16F10 mouse melanoma cells and nude mice transplanted with B16F10 melanoma cells in the presence or absence of CoCl2-induced hypoxia. IDF-11774 reduced HIF-1α upregulation and cell survival, but increased cytotoxicity of cultured melanoma cells under CoCl2-induced hypoxia. IDF-11774 also reduced tumor size and local invasion of B16F10 melanoma in nude mice along with HIF-1α downregulation. Expression levels of cyclin D1 in melanoma were increased by CoCl2 but decreased by IDF-11774. Apoptosis of melanoma cells and infiltration of cytotoxic T cells were increased in melanoma after treatment with IDF-11774. EMT was stimulated by CoCl2, but restored by IDF-11774. Overall, IDF-11774 inhibited the growth and metastasis of B16F10 melanoma via HIF-1α downregulation. The growth of B16F10 melanoma was inhibited by cyclin D1 downregulation and cytotoxic T cell stimulation. Metastasis of B16F10 melanoma was inhibited by EMT suppression.

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“…Engagement of inhibitory immune checkpoint molecules such as Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) on T cells inhibits the glycolysis and amino acid metabolism which is crucial to effector differentiation and function ( 77 ). Hypoxia in the TME can upregulate the ligand for PD-1, Programmed death-ligand 1 (PD-L1) on tumors ( 78 – 81 ), as can glucose-depleted conditions ( 82 ), which engage inhibitory checkpoints on T cells and lead to their “exhaustion”. Even though the TME is known to be immunosuppressive and poor in nutrients, the survival and persistence of infiltrating immune cells is crucial to the sustained effectiveness of TCR-T.…”

Section: Strategies For Improving Functionality and Persistence Of Ad...mentioning

confidence: 99%

Overcoming current challenges to T-cell receptor therapy via metabolic targeting to increase antitumor efficacy, durability, and tolerability

Mao

2022

Front. Immunol.

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The antitumor potential of personalized immunotherapy, including adoptive T-cell therapy, has been shown in both preclinical and clinical studies. Combining cell therapy with targeted metabolic interventions can further enhance therapeutic outcomes in terms of magnitude and durability. The ability of a T cell receptor to recognize peptides derived from tumor neoantigens allows for a robust yet specific response against cancer cells while sparing healthy tissue. However, there exist challenges to adoptive T cell therapy such as a suppressive tumor milieu, the fitness and survival of transferred cells, and tumor escape, all of which can be targeted to further enhance the antitumor potential of T cell receptor-engineered T cell (TCR-T) therapy. Here, we explore current strategies involving metabolic reprogramming of both the tumor microenvironment and the cell product, which can lead to increased T cell proliferation, survival, and anti-tumor cytotoxicity. In addition, we highlight potential metabolic pathways and targets which can be leveraged to improve engraftment of transferred cells and obviate the need for lymphodepletion, while minimizing off-target effects. Metabolic signaling is delicately balanced, and we demonstrate the need for thoughtful and precise interventions that are tailored for the unique characteristics of each tumor. Through improved understanding of the interplay between immunometabolism, tumor resistance, and T cell signaling, we can improve current treatment regimens and open the door to potential synergistic combinations.

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A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma

Cited by 14 publications

References 32 publications

Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia

Immunorthodontics: PD-L1, a Novel Immunomodulator in Cementoblasts, Is Regulated by HIF-1α under Hypoxia

Anti-Tumor Effect of IDF-11774, an Inhibitor of Hypoxia-Inducible Factor-1, on Melanoma

Overcoming current challenges to T-cell receptor therapy via metabolic targeting to increase antitumor efficacy, durability, and tolerability

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