Selenite Induces Posttranscriptional Blockade of HLA-E Expression and Sensitizes Tumor Cells to CD94/NKG2A-Positive NK Cells

Enqvist, Monika; Nilsonne, Gustav; Hammarfjord, Oscar; Wallin, Robert P. A.; Björkström, Niklas K.; Björnstedt, Mikael; Hjerpe, Anders; Ljunggren, Hans‐Gustaf; Dobra, Katalin; Malmberg, Karl‐Johan; Carlsten, Mattias

doi:10.4049/jimmunol.1100610

Cited by 41 publications

(43 citation statements)

References 69 publications

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“…This fits with the idea that the level of surface HLA‐E is mainly regulated through the availability and binding of peptides . Moreover, our data are in‐line with a recent study in which HLA‐E expression was abrogated by selenite, resulting in a decrease in cellular HLA‐E protein expression, whereas RNA levels remained intact , confirming regulation of HLA‐E at the post‐transcriptional level. Interestingly, we observed that the induced level of HLA‐E with peptides was inhibited by CHX.…”

Section: Discussionsupporting

confidence: 90%

Peptide‐induced HLA‐E expression in human PBMCs is dependent on peptide sequence and the HLA‐E genotype

et al. 2015

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Human Leukocyte Antigen (HLA)-E is a low-polymorphic non-classical HLA class I molecule which plays a crucial role in immune surveillance by presentation of peptides to T and natural killer (NK) cells. HLA-E polymorphism is related to HLA-E surface expression and is associated with patient outcome after stem cell transplantation. We aim to investigate the regulation of HLA-E expression level in peripheral blood mononuclear cells (PBMCs) of healthy individuals homozygous for HLA-E*01:01 or HLA-E*01:03, by using a panel of HLA-E binding peptides derived from CMV, Hsp60 and HLA class I. Basal and peptide-induced HLA-E surface expression levels were higher in PBMC from HLA-E*01:03 homozygous subjects as compared to PBMC from HLA-E*01:01 homozygous subjects. HLA-E mRNA levels were comparable between the two genotypes and remained constant after peptide stimulation. HLA-E surface expression seemed to be not only dependent on the HLA-E genotype, but also on the sequence of the peptide as evidenced by the profound difference in HLA-E upregulation with the Hsp60 and the B7 peptide. Our results showed that peptide-induced HLA-E expression is regulated at the posttranscriptional level as extracellular peptide stimulation did not influence RNA expression. This study provides new insights in the mechanism by which HLA-E expression is regulated and underlines a new role for extracellular peptides in inducing HLA-E translation, which may represent a defense mechanism against lytic viral infections and necrosis.

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Section: Discussionsupporting

confidence: 90%

Peptide‐induced HLA‐E expression in human PBMCs is dependent on peptide sequence and the HLA‐E genotype

et al. 2015

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“…Interestingly, the inorganic selenite could both promote cellular apoptosis and block HLA‐E expression in cancer cells of various origins 13. The decrease in the expression level of HLA‐E further renders cancer cells susceptible to NK cells by oxidative stress 14. Seleninic acid (RSeO(OH)) is the oxidation products of diselenide with the same chemical valence of Se as selenite (SeO 3 2− ).…”

Section: Figurementioning

confidence: 99%

Selenium‐Containing Nanoparticles Combine the NK Cells Mediated Immunotherapy with Radiotherapy and Chemotherapy

et al. 2020

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Considering the limited clinical benefits of individual approaches against malignancy, natural killer (NK) cell‐mediated immunotherapy is increasingly utilized in combination with radiotherapy and target therapeutics. However, the interplay of targeted agents, immunotherapy, and radiotherapy is complex. An improved understanding of the effect of chemotherapy or radiotherapy on specific molecular pathways in immune cells would help to optimize the synergistic antitumor efficiency. In this study, the selenium‐containing nanoparticles (NPs) could deliver the chemotherapeutic drug doxorubicin (DOX) to tumor sites by systemic administration. Radiation stimuli facilitate DOX release and enhance chemotherapy efficiency. Moreover, radiation could oxidize diselenide‐containing NPs to seleninic acid, which have both synergistic antitumor effect and immunomodulatory activity through enhancing NK cells function. These results indicate that the selenium‐containing NPs would be a potential approach to achieve simultaneous treatments of immunotherapy, chemotherapy, and radiotherapy by a simple but effective method.

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“…The mechanism of action of selenium is not entirely known, but it induces apoptosis of tumor cells by generating an oxidative stress, which may be more effective on tumor cells compared to healthy cells (118, 119). Alternatively, selenium blocks the synthesis of HLA-E and consequently increases cytotoxicity mediated by NKG2A-positive NK cells (120). This effect, combined to the direct toxicity on tumor cells may result in reduced disease progression and improved survival.…”

Section: Targeting Inhibitory Receptorsmentioning

confidence: 99%

Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity

et al. 2014

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Despite evidence of cancer immune-surveillance, which plays a key role in tumor rejection, cancer cells can escape immune recognition through different mechanisms. Thus, evasion to Natural killer (NK) cell-mediated anti-tumor activity is commonly described and is mediated by various mechanisms, mainly cancer cell-induced down-regulation of NK-activating receptors (NCRs, NKG2D, DNAM-1, and CD16) as well as up-regulation of inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs, NKG2A). Alterations of NK cells lead to an impaired recognition of tumor cells as well as a decreased ability to interact with immune cells. Alternatively, cancer cells downregulate expression of ligands for NK cell-activating receptors and up-regulate expression of the ligands for inhibitory receptors. A better knowledge of the extent and the mechanisms of these defects will allow developing pharmacological strategies to restore NK cell ability to recognize and lyse tumor cells. Combining conventional chemotherapy and immune modulation is a promising approach likely to improve clinical outcome in diverse neoplastic malignancies. Here, we overview experimental approaches as well as strategies already available in the clinics that restore NK cell functionality. Yet successful cancer therapies based on the manipulation of NK cell already have shown efficacy in the context of hematologic malignancies. Additionally, the ability of cytotoxic agents to increase susceptibility of tumors to NK cell lysis has been studied and may require improvement to maximize this effect. More recently, new strategies were developed to specifically restore NK cell phenotype or to stimulate NK cell functions. Overall, pharmacological immune modulation trends to be integrated in therapeutic strategies and should improve anti-tumor effects of conventional cancer therapy.

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Selenite Induces Posttranscriptional Blockade of HLA-E Expression and Sensitizes Tumor Cells to CD94/NKG2A-Positive NK Cells

Cited by 41 publications

References 69 publications

Peptide‐induced HLA‐E expression in human PBMCs is dependent on peptide sequence and the HLA‐E genotype

Peptide‐induced HLA‐E expression in human PBMCs is dependent on peptide sequence and the HLA‐E genotype

Selenium‐Containing Nanoparticles Combine the NK Cells Mediated Immunotherapy with Radiotherapy and Chemotherapy

Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity

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