Natural killer (NK) cells, the effectors of the innate immune system, have a remarkable influence on cancer prognosis and immunotherapy. In this study, a total of 1,816 samples from nine independent cohorts in public datasets were enrolled. We first conducted a comprehensive analysis of single-cell RNA-sequencing data of lung adenocarcinoma (LUAD) from the Gene Expression Omnibus (GEO) database and determined 189 NK cell marker genes. Subsequently, we developed a seven-gene prognostic signature based on NK cell marker genes in the TCGA LUAD cohort, which stratified patients into high-risk and low-risk groups. The predictive power of the signature was well verified in different clinical subgroups and GEO cohorts. With a multivariate analysis, the signature was identified as an independent prognostic factor. Low-risk patients had higher immune cell infiltration states, especially CD8+ T cells and follicular helper T cells. There existed a negative association between inflammatory activities and risk score, and the richness and diversity of the T-cell receptor (TCR) repertoire was higher in the low-risk groups. Importantly, analysis of an independent immunotherapy cohort (IMvigor210) revealed that low-risk patients had better immunotherapy responses and prognosis than high-risk patients. Collectively, our study developed a novel signature based on NK cell marker genes, which had a potent capability to predict the prognosis and immunotherapy response of LUAD patients.

/pdf/identification-and-validation-of-a-novel-signature-based-on-27abvm9z.pdf

Identification and Validation of a Novel Signature Based on NK Cell Marker Genes to Predict Prognosis and Immunotherapy Response in Lung Adenocarcinoma by Integrated Analysis of Single-Cell and Bulk RNA-Sequencing

Current chemotherapy strategies used in clinic appear with lots of disadvantages due to the low targeting effects of drugs and strong side effects, which significantly restricts the drug potency, causes multiple dysfunctions in the body, and even drives the emergence of diseases. Immunotherapy has been proved to boost the body’s innate and adaptive defenses for more effective disease control and treatment. As a trace element, selenium plays vital roles in human health by regulating the antioxidant defense, enzyme activity, and immune response through various specific pathways. Profiting from novel nanotechnology, selenium nanoparticles have been widely developed to reveal great potential in anticancer, antibacterial, and anti-inflammation treatments. More interestingly, increasing evidence has also shown that functional selenium nanoparticles can be applied for potential immunotherapy, which would achieve more effective treatment efficiency as adjunctive therapy strategies for the current chemotherapy. By directly interacting with innate immune cells, such as macrophages, dendritic cells, and natural killer cells, selenium nanoparticles can regulate innate immunity to intervene disease developments, which were reported to boost the anticancer, anti-infection, and anti-inflammation treatments. Moreover, selenium nanoparticles can also activate and recover different T cells for adaptive immunity regulations to enhance their cytotoxic to combat cancer cells, indicating the potential of selenium nanoparticles for potential immunotherapy strategy development. Here, aiming to enhance our understanding of the potential immunotherapy strategy development based on Se NPs, this review will summarize the immunological regulation effects of selenium nanoparticles and the application of selenium nanoparticle-based immunotherapy strategies. Furthermore, we will discuss the advancing perspective of selenium nanoparticle-based potential immunotherapy as a kind of novel adjunctive therapy to enhance the efficiency of current chemotherapies and also introduce the current obstacles for the development of selenium nanoparticles for potential immunotherapy strategy development. This work is expected to promote the future research on selenium nanoparticle-assisted immunotherapy and finally benefit the more effective disease treatments against the threatening cancer and infectious and chronic diseases.

/pdf/immunomodulatory-roles-of-selenium-nanoparticles-novel-arts-1ldiwjoh.pdf

Immunomodulatory roles of selenium nanoparticles: Novel arts for potential immunotherapy strategy development

Selenium (Se) is a necessary micronutrient, while Se-deficiency is common in most areas worldwide. Developing dietary Se-supplements can address this issue. Se-enriched Lentinus edodes are good sources of natural Se-polysaccharides that are promising dietary Se-supplements. However, Se-polysaccharides from Se-enriched Lentinus edodes (Se–P-LE) fruit body via enzymatic-extraction (EE) have only been sparsely studied. Thus, the EE of Se–P-LE was optimized via Box-Behnken and uniform test, and the physicochemical and bio-functional properties of Se–P-LE were investigated herein. The results showed that the optimized EE conditions were: extracting temperature of 45 °C, pH of 4.5, time of 85 min and a liquid-solid ratio of 20:1 mL/g. The addition amount of cellulase, papain and pectinase were 0.80, 0.65 and 0.8 g/100 g samples, respectively. Under this condition, Se–P-LE yield was 18.16 ± 0.10%, and the Se content of Se–P-LE was 29.51 ± 0.23 μg/100 g. Characterization of Se–P-LE showed that Se–P-LE were Se-conjugated polysaccharides with pyranoglycan and β-glycosidic linkages. Se–P-LE were composed of 8 monosaccharides with shear-thinning properties and microcrystalline/amorphous structures. The bioactivities assays showed that Se–P-LE displayed a higher DPPH and hydroxyl radical scavenging rate than ordinary polysaccharides. Besides, Se–P-LE significantly reduced mRNA expression and levels of pro-inflammation factors (NO, IL-6/1β and TNF-α) caused by LPS in RAW264.7 cell line. 

Optimization of enzymatic extraction, characterization and bioactivities of Se-polysaccharides from Se-enriched Lentinus edodes

Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability. 

The mechanism of selenium regulating the permeability of vascular endothelial cells through selenoprotein O

Selenoprotein K (SELENOK) is an endoplasmic reticulum stress (ERS)-regulated protein required for the calcium (Ca2+) flux-mediated migration of T cells and neutrophils, and the migration and phagocytosis of macrophages and microglia. However, the effect of SELENOK on the regulation of the immune function of dendritic cells (DCs), including immature DCs (imDCs) and mature DCs (mDCs), is still unclear. In this study, imDCs prepared from SELENOK knockout mice were used to evaluate the effect of SELENOK on the migration and phagocytosis of imDCs. The results showed that ERS-induced downregulation of imDCs phenotypic markers led to a reduction in Ras homolog gene family member A (RhoA)-dependent migration and enhanced Ca2+/CD205-mediated phagocytosis. SELENOK deficiency-induced upregulation of selenoprotein S (SELENOS) attenuated ERS levels in imDCs. An increase in Ca2+ levels resulted in increased migration and decreased phagocytosis with or without ERS conditions. The migration was RhoA-dependent, and Ca2+ or CD205 was associated with regulating phagocytosis in imDCs. Our study found that SELENOK is required for imDC migration and phagocytosis.

/pdf/selenoprotein-k-is-essential-for-the-migration-and-3hm2u58r.pdf

Selenoprotein K Is Essential for the Migration and Phagocytosis of Immature Dendritic Cells

The administration of mRNA-based tumour vaccines is considered a promising strategy in tumour immunotherapy, although its application against kidney renal clear cell carcinoma (KIRC) is still at its infancy stage. The purpose of this study was to identify potential antigens and to further select suitable patients for vaccination. Gene expression data and clinical information were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. GEPIA2 was used to evaluate the prognostic value of selected antigens. The relationship of antigens presenting cell infiltration with antigen expression was evaluated by TIMER, and immune subtypes were determined using unsupervised cluster analysis. Tumour antigens LRP2 and DOCK8, which are associated with prognosis and tumour-infiltrating antigen-presenting cells, were identified in KIRC. A total of six immune subtypes were identified, and patients with immune subtype 1–4 (IS1–4) tumours had an immune ‘cold’ phenotype, a higher tumour mutation burden, and poor survival. Moreover, these immune subtypes showed significant differences in the expression of immune checkpoint and immunogenic cell death modulators. Finally, the immune landscape of KIRC revealed the immune-related cell components in individual patients. This study suggests that LRP2 and DOCK8 are potential KIRC antigens in the development of mRNA vaccines, and patients with immune subtypes IS1–4 are suitable for vaccination.

/pdf/lrp2-and-dock8-are-potential-antigens-for-mrna-vaccine-2xqssoxl.pdf

LRP2 and DOCK8 Are Potential Antigens for mRNA Vaccine Development in Immunologically ‘Cold’ KIRC Tumours

Background Tumor immune cell infiltration is closely associated with the occurrence and development of tumors. Collagen triple helix repeats containing 1 (CTHRC1), a regulator of collagen expression and cell migration, is involved in the metastasis and invasion of tumors. However, the role of CTHRC1 in breast cancer remains unclear. This study aimed to investigate the prognostic value of CTHRC1, and further explore its association with immune infiltration in breast cancer. Methods CTHRC1 expression pattern and prognostic value were analyzed using ONCOMINE, PrognoScan, GEPIA, and Kaplan–Meier Plotter databases. We then detected CTHRC1 mRNA levels in breast cancer tissues and paired normal breast tissues by Q-PCR. Subsequently, the University of California Santa Cruz (UCSC) database was used to determine the methylation status of CTHRC1. Furthermore, CTHRC1 mutations were investigated using the Catalogue of Somatic mutations in Cancer (COSMIC) and cBioPortal databases. We also assessed the correlation between CTHRC1 expression and immune cell infiltration using TIMER. In addition, The relationship of CTHRC1 expression with the immune marker sets of various immune cells was evaluated using GEPIA and TIMER. Results CTHRC1 was highly expressed in a variety of tumors, including breast cancer. Elevated CTHRC1 expression was related to a poor prognosis. Notably, CTHRC1 expression was significantly associated with macrophage infiltration, especially the immune infiltration gene marker set of M2. Copy number variations, DNA mutations and methylation states might be potential mechanisms for regulating CTHRC1 expression. Protein digestion and absorption, human papillomavirus infection, ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways were identified as the potential CTHRC1-driven signaling pathways. Conclusion These findings suggest that CTHRC1 could be a promising immune-related biomarker for the treatment of breast cancer patients.

https://www.dovepress.com/getfile.php?fileID=81609

CTHRC1 is a Potential Prognostic Biomarker and Correlated with Macrophage Infiltration in Breast Cancer

Identification of M2 macrophage markers for predicting outcome and therapeutic response in osteosarcoma: Integrated analysis of single-cell and bulk RNA-sequencing

Effects of dietary selenium on immune function of spleen in mice

Selenium levels can regulate the function of T cells, macrophages, B cells, natural killer cells and other immune cells. However, the effect of selenium on the immune function of dendritic cells (DCs) isolated from selenium-supplemented mice is unknown. In this study, C57BL/6J mice were randomly divided into three groups and fed diets containing low (0.08 ppm), medium (0.25 ppm) or high (1 ppm) selenium levels for 8 weeks. Immature (imDCs) and mature (mDCs) dendritic cells were then isolated from the bone marrow. Next, the migration, phagocytic capacity and mixed lymphocyte reaction (MLR) for imDCs and mDCs were detected by transwell and flow cytometry. The levels of C-C chemokine receptor type 7 (CCR7), major histocompatibility complex II (MHCII) and reactive oxygen species (ROS) were assayed by flow cytometry. F-actin and superoxide dismutase (SOD) activity was detected by fluorescence microscopy and SOD assay kit, respectively. In addition, the extracellular signal-regulated kinase (ERK), Akt, Ras homolog gene family member A/Rho-associated protein kinase (RhoA/ROCK) signalling, selenoprotein K (SELENOK) and glutathione peroxidase 1 (GPX1) levels were measured by western blot analysis. The results indicated that selenium deficiency enhanced the migration of imDCs by ROS and SELENOK-mediated ERK, Akt and RhoA/ROCK pathways but impaired the antigen uptake of imDCs. Although a high selenium level inhibited the migration of imDCs, it had no effect on phagocytic capacity. For mDCs, low selenium levels impaired free migration, and high levels inhibited the chemotactic migration involved in F-actin and CCR7, respectively. Low and high selenium levels impaired the MLR by inhibiting MHCII surface localisation, which might be related to ROS- and SELENOK-mediated ERK, Akt and RhoA/ROCK signalling pathways. In summary, selenium may regulate the immune function of mouse DCs through the ROS- and SELENOK-mediated ERK, Akt and RhoA/ROCK signalling.

Selenium Regulation of the Immune Function of Dendritic Cells in Mice Through the ERK, Akt and RhoA/ROCK Pathways

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