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Se is an essential element for regulating immune functions.
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Se reverses immunosuppression in the tumour microenvironment.
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Effects of Se on cancer immunity are neglected and require more detailed studies.
Abstract
Selenium is an essential trace element for regulating immune functions through redox-regulating activity of selenoproteins (e.g. glutathione peroxidase), protecting immune cells from oxidative stress. However, in cancer, selenium has biological bimodal action depending on the concentration. At nutritional low doses, selenium, depending on its form, may act as an antioxidant, protecting against oxidative stress, supporting cell survival and growth, thus, plays a chemo-preventive role; while, at supra-nutritional higher pharmacological doses, selenium acts as pro-oxidant inducing redox signalling and cell death. To date, many studies have been conducted on the benefits of selenium intake in reducing the risk of cancer incidence at the nutritional level, indicating that likely selenium functions as an immunostimulator, i.e. reversing the immunosuppression in tumour microenvironment towards antitumour immunity by activating immune cells (e.g. M1 macrophages and CD8+ T-lymphocytes) and releasing pro-inflammatory cytokines such as interferon-gamma; whereas, fewer studies have explored the effects of supra-nutritional or pharmacological doses of selenium in cancer immunity. This review, thus, systematically analyses the current knowledge about how selenium stimulates the immune system against cancer and lay the groundwork for future research. Such knowledge can be promising to design combinatorial therapies with Selenium-based compounds and other modalities like immunotherapy to lower the adverse effects and increase the efficacy of treatments.
]. Se is an essential trace element with substantial importance for human health, including muscle function, the male reproductive biology, cardiovascular, endocrine, nervous and particularly immune systems [
This review constitutes the summarised status of the current knowledge in preclinical studies and clinical trials on how Se affects immunity in cancer, aiming to provoke thoughts and lay the groundwork for future research.
1.1 Selenium and cancer
The influence of Se on malignant transformation, tumour growth and progression depends on the concentration/dose and chemical form of selenium compounds [
]. Three forms of Se compound most important in cancer prevention are sodium selenite (Na2SeO3), l-selenomethionine (C5H11NO2Se) and Se-methylselenocysteine, which differ in their metabolic pathway and reducing cancer risk [
]. Briefly, Se biologically serves as a double-edged sword, either as an anti-oxidant through selenoproteins at nutritional levels or pro-oxidant at supra-nutritional levels (Fig. 1) [
Fig. 1Selenium paradox, Se at nutritional levels or low concentrations are required for cell homeostasis, playing a role as an anti-oxidant through selenoproteins, thus, act chemo-preventive against cancer. In contrast, supra-nutritional levels or higher concentrations act as pro-oxidant in tumour cells, thus can be exploited as chemo-therapeutic against cancer [
]. At nutritional levels, defined as the amount sufficient to saturate selenoproteins, Se functions as an anti-oxidant and plays a possible chemo-preventive role against cancer through scavenging reactive oxygen species (ROS); thereby, preventing damage to the DNA and the occurrence of mutations [
]. The effects of Se status on cancer have been studied in several clinical trials and epidemiologic studies in humans, suggesting beneficial effects of higher Se status in preventing the recurrence of lung cancer [
]. Furthermore, the nutritional prevention of cancer trial demonstrated that Se-enriched yeast reduced the incidence and mortality of colorectal, prostate and lung cancers [
]. Recently, a human intervention study involving more than 300 lung cancer patients showed that Se seral level over 69 μg L−1 is significantly associated with improved overall survival [
1.1.2 Selenium: chemo-therapeutic at supra-nutritional level
In contrast, supra-nutritional levels or pharmacological doses of either redox-active Se compounds (e.g. selenite) or redox-active Se metabolites (e.g. selenide) react with thiols and oxygen causing oxidative stress, i.e. pharmacological doses of Se plays a pro-oxidative role against cancer [
]. For example, we showed that drug-resistant malignant cells (e.g. lung cancer cells) are more sensitive to pharmacological doses of selenite compared to normal cells [
]. The suggested mechanism includes targeting the resistant phenotype comprising increased levels of thiols, induction of redox-enzymes, a higher metabolic rate and induction of a capacity to metabolise and remove xenobiotics (e.g. cytostatic drugs) [
Extracellular thiol-assisted selenium uptake dependent on the xc cystine transporter explains the cancer-specific cytotoxicity of selenite. vol. 106. 2009: 11400-11405
]. These mechanisms include membrane pumps such as the multidrug resistance protein (MRP) superfamily, system xc− cystine/glutamate antiporter and high intracellular levels of glutathione [
Extracellular thiol-assisted selenium uptake dependent on the xc cystine transporter explains the cancer-specific cytotoxicity of selenite. vol. 106. 2009: 11400-11405
], i.e. the MRP and the antiporter system xc− accelerate Se uptake resulting in a higher accumulation of Se in malignant cells compared to normal cells. The higher levels of glutathione and intracellular thiols, along with a higher metabolic rate and oxygen supply in the tumour microenvironment (TME), facilitate redox cycles between selenide or monomethylselenol, oxygen and thiols resulting in non-stoichiometric oxidative stress in tumour cells [
]. Overall, Se has tremendous potential to be used as a cancer chemo-therapeutics, but thus far, only a few clinical trials have been conducted to evaluate the pharmacological effect of Se in cancer. In 2015, we published the first-in-man systematic phase I clinical trial using sodium selenite in patients with cancer (IV to end-stage) demonstrating high tolerance; the maximum tolerated dose was determined as 10.2 mg m−2 body surface area [
The immunomodulatory effects of Se are considered to be mainly due to the diverse activity of selenoproteins, particularly their roles in redox homeostasis [
]. The anti-oxidant effects of Se are proposed to be mediated mainly through selenoproteins utilising their selenocysteine (U) residues to catalyse redox-based reactions in the cell, blood and intestine [
]. For instance, it has been indicated that selenophilic cancer cells (e.g. breast cancer cells) have higher levels of selenoproteins protecting them against ferroptosis [
]. The selenoprotein-enzymes (syn. selenoenzymes) such as glutathione peroxidases (GPxs) 1–4 and 6, thioredoxin reductases (TXNRDs) 1–3, methionine-R-sulfoxide reductase B1 (MSRB1), iodothyronine deiodinases (DIOs) 1–3 and selenophosphate synthetase 2 (SEPHS2), affect immune functions. In addition, the non-enzymatic selenoprotein K (SELENOK), an endoplasmic reticulum (ER) transmembrane protein, plays an important role in ER stress, calcium flux, the activation and proliferation of immune cells [
]. For example, In SELENOK knockout mice, immune system development was not affected; however, Ca2+-dependent functions such as T lymphocytes proliferation/migration, neutrophil migration and Fcγ receptor-mediated ROS in macrophages were decreased [
], i.e. immunostimulatory effects of Se can be seen as supplementation raises the levels of Se from insufficient to adequate; whereas, the advantages of raising the amount of Se to supra-nutritional levels on the immune system are less clear [
Consumption of selenium-enriched broccoli increases cytokine production in human peripheral blood mononuclear cells stimulated ex vivo, a preliminary human intervention study.
]. Adequate or above-adequate supplementation of Se is essential for regulating proper immune responses. For instance, Se is incorporated into selenoenzymes with anti-oxidant function (e.g. GPxs) to catalyze the reduction of peroxides, providing protection against ROS. Furthermore, other selenoproteins, such as the TXNRDs and MSRB1, play substantial roles in regulating redox activity and restoring the immune cells damaged by oxidative stress [
]. For example, adequate levels of Se in healthy mice are essential to promote the expression of selenoproteins, interferon (IFN)γ and interleukin (IL)−6 [
]. Furthermore, a human intervention study showed that consumption of Se-enriched foods (200 μg per serving for 3 days) increases the levels of interleukin IL-2, IL-4, IL-5, IL-13 and IL-22, indicating an activated Th2-type response [
Consumption of selenium-enriched broccoli increases cytokine production in human peripheral blood mononuclear cells stimulated ex vivo, a preliminary human intervention study.
Fig. 2Supplementation of Se affects innate immunity; neutrophils, increasing of selenoproteins protect from oxidative stress; macrophages, increasing of migration and phagocytotic activity and switching to anti-inflammatory M2 type; NK cells, increasing lytic activity and pro-inflammatory cytokines. Se supplementation also affects adaptive immunity through recruiting Th1 T-lymphocytes, releasing pro-inflammatory cytokines. In contrast, Se deficiency affects humoral immunity; B-lymphocytes by decreasing amounts of IgG and IgM. A green upward-facing arrow (↑) indicates that the trend value is increasing, while a red downward-facing arrow (↓) indicates the trend value is decreasing.
In non-malignant conditions, Se supplementation to (Se-deficient) macrophages attenuates pro-inflammatory functions of macrophages by switching the macrophage activation from pro-inflammatory phenotype M1 towards the anti-inflammatory phenotype M2 [
]. As a consequence, it is theoretically expected that M2 phenotype of macrophages secretes anti-inflammatory cytokines such as IL-10 suppressing tumour growth [
]. Serum selenium concentrations were positively associated with the increased number and activity of natural killer (NK) cells in elderly individuals [
]. Also, dietary Se intake augmented the cytotoxic functions of NK cells in mice through increased expression of IL-2 receptors (IL-2R) on the surface of NK cells resulted in the elevated lytic activity of activated NK cells and enhanced proliferation and clonal expansion of cytotoxic precursor cells [
]. Consequently, it is expected that activated NK cells exhibit cytotoxicity against various neoplastic cells and secrete immunoregulatory cytokines, e.g. IFNγ and TNFα [
In vitro study showed that Se could influence immune function by enhancing the levels of ROS or glutathione, which subsequently activate extracellular signal-regulated kinases (ERK) and promoting antigen phagocytosis in immature dendritic cells (DCs). Furthermore, the expression of matrix metalloproteinases is decreased to inhibit chemotactic migration [
]. However, the effect of Se on ROS scavengers is dependent on the Se exposure level. In this regard, an excess dose of Se reduced the antioxidant activity of multiple enzymes involved in redox control, including glutathione peroxidase (GPx), catalase, superoxide dismutase and glutathione reductase [
]. Noteworthily, the impact of Se on immunity through the regulation of the ROS pathway is a double-edged sword, i.e. prolonged Se-mediated ROS either contributes to the stimulation of immune response (mainly through DCs) or diminishes the effector functions and integrity of the prominent components of antitumour immunity, e.g. cytotoxic T-lymphocytes [
]. Se intake also affects humoral immunity; for instance, immunoglobulin (Ig)G and IgM titres secreted from B-lymphocytes are decreased due to Se deficiency in humans [
]. Se is required for optimal immune function, and many studies have revealed the significance of Se for the immune response at nutritional levels, particularly in viral infection. The immune-boosting effects of Se supplementation can also be a mechanism through which Se lowers the incidence and mortality of cancer; however, limited studies have investigated the relation of Se and anti-cancer immunity. Particularly, the mechanisms of how Se affects the immune system and cancer immunity are not fully understood yet.
2. Selenium affects immune cells in cancer
In the TME, immune suppressive and tumour cells release tumour promoting factors such as IL-1, IL-8, TNFα, TNFβ, TGFβ and vascular endothelial growth factor (VEGF) reprogramming macrophage function and polarisation towards anti-inflammatory and pro-tumoral identity, i.e. TME acts in an immunosuppressive manner by turning the balance of macrophages from pro-inflammatory M1 phenotype towards anti-inflammatory tumour-associated macrophages (TAMs) M2 phenotype. In many tumours, the total tumour mass is composed of 10%–50% TAMs, favouring tumour growth and angiogenesis [
]. Noteworthily, Se supplementation impacts both innate immune cells (incl. neutrophils, macrophages and NK cells), as well as adaptive immune cells, particularly T-lymphocytes in the TME (Table 1, Table 2).
Table 1List of clinical studies evaluated the effects of Se on antitumour immunity.
Cancer Type
Cohort
Se baseline (normal: 40_150 μg L−1)
Effects on the immune system
Ref.
Cytotoxicity of lymphocytes tested on K562 leukaemia cell line in vitro
Clinical (32 healthy individuals)
10_14 μg dL−1
Sodium selenite (200 μg.day−1 for 8 weeks) increased the CD8+ T-lymphocyte-mediated tumour cytotoxicity and NK cell activity by 118% and 82%, respectively. Also, enhanced the expression of IL2-R.
Selenium glycinate (100 μg.day−1 for 1 month) increased the neutrophil count in all patients during chemotherapy. Also, reduced levels of IgG and IgA in all patients, whereas increased levels of IgE in patients with leukaemia/lymphoma.
Biopsy transcriptomics and proteomics (22 individuals)
Optimal group: 1.43 mM Suboptimal group: 0.86 mM
Genes involved in immune responses exhibited the largest fold changes in expression (e.g. HLA-A29.1 and HLA-DRB1), growth factors and cytokines (BMP4, CCL12, CCL19, IL-1B and IL-8), and inflammatory proteins (e.g. ApoA1). Gene expression of NFκB, IL-1, TNFα and Akt was correlated with Se status highlighting their central regulatory role in inflammation. Thus, Se status affects immune pathways associated with inflammatory signalling.
Sodium selenite diet (2 ppm) enhanced the lytic activity of activated NK cells. Increased expression of intermediate IL-2R in cells and augmented the proliferation, expansion and lytic activity of lymphokine-activated killer cells.
Sodium selenite (2 ppm) reduced the size of tumours. Also, peritumoural injections of IL-2 (2000 IU) reduced the size of tumours (50%–72%), suggesting that combinational therapy of Se with IL-2 is an effective treatment.
Oral administration of SeNPs, composed of sodium selenite (100 μg.day−1), enhanced Th1 immunity and levels of Th1 cytokines, including IFNγ, IL-2, IL-12 and TNFα; whereas reduced CD4+ T-lymphocytes and myeloid-derived suppressor.
Oral administration of SeNPs dose-dependently (50_200 μg) increased seral IFNγ and the ratio of IFNγ/IL-4. Also, it reduced tumour volume and extended life span.
Methylselenol, a selenium metabolite, upregulated the expression of NKG2D ligands in malignant cells, resulting in the recognition and elimination of malignant cells by NKG2D-expressing NK cells.
Methylseleninic acid (2.5 μM) increased levels of MHC-I cell surface antigens on cancer cells, improving their detection by CD8+ T-lymphocytes. Additionally, methylselenol mimic IFNγ signalling by upregulating members of the IFNγ pathway followed by a reduced migration of melanoma cells.
Hepatocellular carcinoma cell lines (Huh7 and HCC-3)
Mouse in vivo and patient’s data metanalysis
In patients, GPx4 expression in tumours correlates with survival and regulates cell proliferation, immune response, M1 macrophage polarisation, motility and tissue remodelling. In immune-deficient non-diabetic mice, overexpression of GPx4 decreased tumour growth, reduced proliferation, angiogenesis and expression of IL-8 and C-reactive protein.
Neither selenite nor methylseleninic acid (5 μM) influenced the viability of immune cells at cytotoxic doses in ovarian cancer cell lines. But increased NK cell-mediated lysis and the cytolytic activity of T cells. Methylseleninic acid enhanced T cell function against tumour cells that was coupled with decreased levels of HIF-1α, PD-L1 and VEGF.
Se-enriched chickpea sprouts containing high Se (2 μg g−1) increased GPxs and TXNRDs activities, decreased tumour growth and stimulated apoptotic cell death through the overexpression of Fas death receptor on the cell surface.
Chickpea (Cicer arietinum L.) sprouts containing supranutritional levels of selenium decrease tumor growth of colon cancer cells xenografted in immune-suppressed mice.
Subtoxic dose pre-treatment with Se-bearing ruthenium (40 μM) upregulated IFNγ and IL-2 and downregulated expression of TGFβ; stimulated the lytic activity of NK cells, 3-fold higher than NK cells alone, through TRAIL/TRAIL-R and Fas/FasL-mediated signalling. Furthermore, ROS generation triggered DNA damage.
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
SeNPs (1_8 μM), composed of sodium selenite, prolonged the in vivo persistence of cytokine-induced killer (CIK) cells by inducing IL-15 and inhibiting apoptotic cell death; enhanced the cytotoxicity of CIK cells through upregulating the expression of NKG2D receptor and ligands, induced infiltration of NK cells in tumours and polarised TAMs towards the M1 phenotype. SeNPs also downregulated the expression of PD-1 and PD-L1 on CIK and tumour cells, relieving the exhaustion of immune cells. SeNPs upregulated the expressions of selenoproteins K, O, P, R, S, T, W, GPx2, TXNRD1 and Sep15 in HepG2 cells. SeNPs enhanced the production of pro-inflammatory cytokines (e.g. IFNγ), whereas downregulated the expression of anti-inflammatory cytokines (e.g. IL-10 and TGFβ) by CIK cells.
SeNPs (100 μg. mL−1) stimulate macrophage immunity by increasing the gene expression of IFNγ, IL-12, IL-27 and MHC-I. Thus, increased cytotoxic activity of phagocytotic macrophages against tumour lysates.
Non-crystalline SeNPs (10 mg kg−1) enhanced the release of cytokines (IFNγ, IL-6 and IL-12/23) and T-lymphocytes, consequently inhibited the growth of secondary tumours.
Se intake increases M1 macrophages with antitumour activity in the TME (Table 2). It has been shown that selenium nanoparticles (SeNP)s in pharmacological doses induces ROS generation, the expression of fusion receptors (CD47 and CD172α), adhesion molecules (CD54 and ICAM-1) and the formation of macrophage polykaryons on TAMs; thus, inducing the antitumour function of TAMs and inhibiting tumour cell proliferation [
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
]. For instance, mechanistic studies showed that the sensitising effect of Se-bearing ruthenium is dependent on TRAIL/TRAIL-R and Fas/FasL-mediated signalling, which relies on ROS-triggered DNA damage and the downstream Ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) signalling pathways [
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
] (Table 1, Table 2). In addition, Se increases the expression levels of MHC-I antigens on cancer cells in vitro, thus, improving their detection and destruction by CD8+ T-lymphocytes [
] (Table 2). Furthermore, an in vitro study showed that methylseleninic acid-enhanced T cell-mediated killing of ovarian cancer cells via PD-L1 and VEGF inhibition [
Se status is mostly correlated with levels of pro-inflammatory cytokines in cancer. For example, levels of IFNγ were increased after Se supplementation [
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
]. The ratio of IFNγ/IL-4 was also increased in serum following oral administration of Se in mice, indicating a turn of the balance towards pro-inflammatory cytokines [
]. In an in vitro study, methylseleninic acid inhibited the growth of melanoma cells by upregulation of MHC class I antigen due to an altered redox status and by mimicking the IFNγ signalling pathway, thereby reverting immune escape [
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
]. In contrast, one randomised chemoprevention trial showed that selenomethionine supplementation decreased seral IL-2 levels. It was then suggested that the favourable effect of selenomethionine on oesophageal dysplasia had been mediated by reducing the levels of IL-2 [
Chickpea (Cicer arietinum L.) sprouts containing supranutritional levels of selenium decrease tumor growth of colon cancer cells xenografted in immune-suppressed mice.
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
] were downregulated (Table 1, Table 2). In the wake of upregulation of IL-12 and downregulation of IL-10, it can then be assumed that Se influences the maturation of DCs and their ability to stimulate Th1 immune response because mature DCs release large amounts of IL-12, which can stimulate a Th1 immune response. In contrast, the release of IL-10 blocks the dendritic maturation process and subsequently limiting the ability of DCs to initiate a Th1 response [
Mechanistically, the TME works in favour of tumour progression and angiogenesis by switching to M2 TAMs, releasing immuno-suppressive/anti-inflammatory factors such as IL-4 and IL-10 [
]. Moreover, the TME contains a high number of CD4+ T-lymphocytes, also known as T regulatory (Treg) cells, suppressing the antitumour response. Two subsets of the CD4+ T-lymphocytes, including Th2 (releasing IL-4, IL-5, IL-13) and Th17 (releasing IL-17A, IL-17F, IL-21 and IL-22), are associated with tumorigenesis and inflammation [
]. Se, however, reverses the immunosuppression in the TME towards pro-inflammatory antitumour immunity. For example, An in vivo study of melanoma and breast cancer showed that higher Se intake leads to lesser tumour growth due to suppression of antitumour immunity [
]. Increasing Th1-type in the TME, thus, provides the framework for clinical studies to treat cancer with Selenium-based compounds. Combinational therapies for Se with other treatment modalities may be effective, such as combining Se and IL-2 in future clinical trials [
]; modifying these pathways may theoretically serve as a portal for therapy. Se, through selenoproteins, regulates redox homeostasis and inflammatory pathways in cells. Hence, Se can influence the interaction between tumour and immune cells in the TME [
]; this information may elucidate the appropriate uses of Se for treating cancer in the clinical stage. For instance, It has been shown that over-expression of thiols in CD8+ T-cells is inversely correlated with the generation of ROS, promoting the reductive cellular environment, thereby resulting in the extended durability of antitumour CD8+ T-cells function, with implications for adoptive immunotherapies such as CAR T-cell therapy [
]. Hence, Se, as an antioxidant, can potentially increase the efficacy of CAR T-cell therapy in a combinational regimen by protecting CAR T-cells from oxidative damage.
3.2 Bimodal actions of selenium
The role of Se as either an anti-oxidant or a toxic pro-oxidant have been under debate extensively [
]. Se can function as both pro-oxidant and antioxidant in cells. For example, Se-deficiency may lead to oxidative stress due to reduced levels of selenoproteins such as GPx and TXNRD. In contrast, an overdose of Se may induce a redox shift by oxidising, cross-linking of protein thiol groups and elevating ROS generation, resulting in cell death [
Chickpea (Cicer arietinum L.) sprouts containing supranutritional levels of selenium decrease tumor growth of colon cancer cells xenografted in immune-suppressed mice.
]. In addition, enhanced dietary Se increases the expression of some selenoproteins. For example, T-lymphocytes from mice exhibited higher GPx1 and TXNRD1 activity with higher Se status [
], we can hypothesise that Se may activate NF-κB and downstream inflammatory pathways through enhanced activity of antioxidant selenoproteins (Fig. 3).
Fig. 3The hypothetical scheme indicating Se induces the pro-inflammatory response in the tumour microenvironment and cancer cells. Se can either play a pro-oxidant role inducing ROS, activating the Akt–NF–кB pathway or play an antioxidant role through selenoprotein synthesis such as TXNRD relocating to the nucleus and activating NF-кB, resulting in further activation of leukocytes and pro-inflammatory cytokine genes.
In addition, ROS activation can play a double-edged sword in cancer. The moderate generation of ROS leads to cancer progression through signalling pathways (e.g. PI3/Akt/mTOR, PTEN, MAPK and VEGF/VEGFR) [
]. In contrast, high ROS generation attenuates cancer progression by initiating apoptosis via activation of the NF-κB pathway by targeting upstream kinases (e.g. IKK, NIK and Akt), which subsequently trigger the secretion of pro-inflammatory cytokines [
]. Comparably, the cytotoxic mechanism and cytokine expression in cancer might follow a similar pattern after treatment with pharmacological/supra-nutritional levels of Se. Thus, even if presumed Se plays a toxic pro-oxidant role in cancer cells, Se can still stimulate pro-inflammatory responses through the activation of the NF-κB pathway as an alternative hypothesis, i.e. Se, either as an antioxidant or pro-oxidant, can theoretically induce a pro-inflammatory response in the cell through NF-κB activation (Fig. 3). Mechanistic studies are, however, required to discover the pathways involved in NF-κB activation by Se.
3.3 Strengths and limitations: future research
To facilitate the study of Se and cancer, rodent models can provide data easier to interpret. It is still, however, difficult to differentiate between the effects of bioavailable Se on cancer cells versus immune cells [
]. When analysing the results of rodent cancer studies, there are also many factors to consider, including strain, cancer type and immune status of the rodents, the dosage and form of Se compound and the endpoints of analysis. The contradictory results of rodent cancer studies in which tumour progression is the primary endpoint for murine studies indicate this problem. The generation of new xenograft and humanised murine models can, therefore, accelerate in vivo studies in the future [
]; however, direct effects of Se on tumours in humans and particularly the effects of Se on the immunity are less clear, i.e. from the clinical perspective, it is difficult to distinguish the direct effects that Se has on the growth of established tumours versus its impact on cancer immunity [
]. Despite the promising effects of Se in cancer, applying wide-scale Se supplementation to enhance immunity in the general population has not yet been supported by the scientific consensus [
]. Because it is still unclear why all immune responses are unequally affected by increasing Se status. The next rational step of research should be, thus, to identify redox sensing, signalling pathways, protein-folding, epigenetic posing and immune cell functions regulated by Se [
In order to prescribe the appropriate level of Se supplementation, evaluation of the baseline Se status of individuals is required within populations. In such a sense, Se supplementation could be administered in a manner of personalised medicine [
], i.e. novel formulations, such as SeNPs, can decrease the dosage of Se and minimise the development of adverse side-effects, e.g. disrupted glucose metabolism [
] demonstrated in vivo evidence that cotreatment of SeNPs with CIK cells might present efficient cancer immunotherapy with clinical application in the future; however, the safety of such nanoparticles for application in humans should first be evaluated.
4. Concluding remarks
Se has bimodal biological action depending on the concentration. At low nutritional doses, Se act as an antioxidant through selenoproteins, scavenging ROS, supporting cell survival and growth; while, at supra-nutritional higher pharmacological doses, Se acts as a pro-oxidant generating ROS and inducing cell death. In cancer, studies have been conducted mostly on the benefits of Se intake in reducing the risk of cancer incidence at the nutritional level; however, fewer studies have explored the effects of supra-nutritional or pharmacological doses of Se on cancer. Particularly, the effects of Se on cancer immunity are mainly neglected and require more attention in the future because Se is largely known as an essential element for regulating immune functions through the antioxidant activity of selenoproteins, protecting immune cells from oxidative stress. Thus far, studies, which investigated the effects of Se at the nutritional level on cancer immunity indicate that Se likely functions as immunostimulatory, i.e. reversing the immunosuppression in the TME towards antitumour immunity by activating immune cells (e.g. CD8+ T-lymphocytes, M1 macrophages, the elevated number of neutrophils and activated cytotoxic NK cells) and releasing pro-inflammatory cytokines (e.g. IFNγ and TNFα). In the future, more detailed studies are needed to elucidate the pathways, immune cells and cytokines involved in immunostimulatory effects of Se in the TME, particularly at the clinical and pharmacological stages. Such knowledge on immune-enhancing effects of Se can be promising to design combinational therapies with selenocompounds and other modalities (e.g. immunotherapy) to lower the adverse effects and increase the efficacy of treatments.
This study was supported by Cancerfonden, Cancer och Allergifonden, Radiumhemmets Forskningsfonder and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest statement
M.B. is listed as an inventor in a patent application for i.v. use of inorganic selenium in cancer patients and holds shares in SELEQ OY, a company involved in the development of Se-based formulations for prevention and treatment.
All remaining authors have declared no conflicts of interest.
References
Whanger P.D.
Selenium and its relationship to cancer: an update.
Extracellular thiol-assisted selenium uptake dependent on the xc cystine transporter explains the cancer-specific cytotoxicity of selenite. vol. 106. 2009: 11400-11405
Consumption of selenium-enriched broccoli increases cytokine production in human peripheral blood mononuclear cells stimulated ex vivo, a preliminary human intervention study.
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
Chickpea (Cicer arietinum L.) sprouts containing supranutritional levels of selenium decrease tumor growth of colon cancer cells xenografted in immune-suppressed mice.
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