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Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy.

Changes in the intestinal microbiota indirectly impact the health of mucosa distal to the intestine, particularly the respiratory tract. However, the effects of intestinal microbiota dysbiosis on the regulation of respiratory syncytial virus (RSV) infection are not clear. In this study, we examined the effects of altering the intestinal microbiota on the pulmonary immune response against RSV infection. BALB/c mice were treated with streptomycin before infection with RSV to study the altered immune response. The ingestion of streptomycin led to a marked alteration in the intestinal microbiota with a reduced abundance of Lactobacillus and Clostridium genera, followed by greatly aggravated pulmonary inflammation in response to RSV infection. This aggravated inflammation was associated with a dysregulated immune response against RSV infection, characterized by the increased expression of IFN-γ and IL-17 and increased pulmonary M1-like macrophage polarization, and decreased expression of IL-5. Supplementation of Clostridium butyricum (CB) prevented aggravated inflammation and the dysregulated immune response characterized by greater M2 polarization of pulmonary macrophages and decreased release of IFN-γ and IL-17 as well as increased IL-5 levels. Furthermore, in vitro and in vivo experiments identified that butyrate, the main metabolite produced by CB, promoted M2 polarization of macrophages in RSV-infected mice exposed to streptomycin. Together, these results demonstrate the mechanism by which intestinal microbiota modulate the pulmonary immune response to RSV infection.

Tuberculosis continues to be an important public health problem. Particularly considering Beijing-family strains of Mycobacterium tuberculosis, which have been associated with drug-resistance and hypervirulence. The Beijing-like SIT190 (BL) is the most prevalent Beijing strain in Colombia. The pathogenic mechanism and immune response against this pathogen is unknown. Thus, we compared the course of pulmonary TB in BALB/c mice infected with Classical-Beijing strain 391 and BL strain 323. The disease course was different among infected animals with Classical-Beijing and BL strain. Mice infected with BL had a 100% mortality at 45 days post-infection (dpi), with high bacillary loads and massive pneumonia, whereas infected animals with Classical-Beijing survived until 60 dpi and showed extensive pneumonia and necrosis. Lung RNA extraction was carried out at early (day 3 dpi), intermediate (day 14 dpi), and late (days 28 and 60 dpi) time points of infection. Transcriptional analysis of infected mice with Classical-Beijing showed several over-expressed genes, associated with a pro-inflammatory profile, including those for coding for CCL3 and CCL4 chemokines, both biomarkers of disease severity. Conversely, mice infected with BL displayed a profile which included the over-expression of several genes associated with immune-suppression, including Nkiras, Dleu2, and Sphk2, highlighting an anti-inflammatory milieu which would allow high bacterial replication followed by an intense inflammatory response. In summary, both Beijing strains induced a non-protective immune response which induced extensive tissue damage, BL strain induced rapidly extensive pneumonia and death, whereas Classical-Beijing strain produced slower extensive pneumonia later associated with extensive necrosis. Abbreviations Mtb: Mycobacterium tuberculosis; SIT: Spoligotype International Type; TB: Tuberculosis; CTB: Classical-typical Beijing; BL: Beijing-Like; CCL3: Chemokine (C-C motif) ligand 3 (CCL3); CCL4: Chemokine (C-C motif) ligand four (CCL4); WHO: World health Organization; DR: Direct Repeats; IFN-γ: Interferon Gamma; IL: Interleukin; TGF-β: Transforming Growth Factor Beta; XDR: Extremely Drug Resistant; MDR: Multi Drug Resistant; MIRU-VNTR: Mycobacterial Interspersed Repetitive Units–Variable Number Tandem repeats; OADC: Oleic Albumin Dextrose Catalase; ATCC: American Type Culture Collection; MOI: Multiplicity of Infection; CFUs: Colony Forming Units; ELISA: enzyme-linked immunosorbent assay; qRT-PCR: Real-Time Quantitative Reverse Transcription PCR; RNA-seq: Ribonucleic Acid sequencing; RIN: RNA Integrity Number; RNA: Ribonucleic Acid; DNA: Deoxyribonucleic Acid; dsDNA HS: Double stranded Deoxyribonucleic Acid High Sensitivity; RAI: Red de Apoyo à la Investigacion, Mexico City, Mexico; DEG: Differential Expressed Genes; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; ORA: Over-Representation Analysis; SNPs: Single Nucleotide Polymorphisms; TNFα: Tumoral necrosis factor alpha; DE: Differential Expression; EPA: Enrichment Pathways Analysis; TLR: Toll-Like receptor; NLRP: NOD-like receptor with Pyrin domain; tRNA: Transfer RNA; MAPK: Mitogen-Activated Protein Kinase; NK: Natural killer; ATP: Adenosine Triphosphate; DGC: dystrophin-glycoprotein complex; PDIM: Ptiocerol Dimicocerosate; NCBI: National Center for Bioinformatics Information

In recent years, Bovine herpesvirus 4 (BoHV-4) has emerged as an attractive gene delivery viral vector, mainly for vaccination purposes in the veterinary field. In the present study, a new infectious clone of the BoHV-4 genome carrying a bacterial artificial chromosome vector (BoHV-4-BAC) was developed by homologous recombination in mammalian cell culture and bacterial systems, and exploited to express a truncated form of glycoprotein D (tgD) of Bovine herpesvirus 1 (BoHV-1) (BoHV-4-tgD∆TK) as a vaccine candidate. This construct's immunogenicity was compared to a DNA vector expressing the same antigen (pC-tgD) in a BALB/c mouse model. After the mice were immunized, total and specific antibody responses, cytokine responses, total splenocyte cells proliferation/cytotoxicity, and virus neutralization assays were conducted to analyze the immune response elicited by both constructs. Mice from both vaccine groups developed significant humoral and cellular immune responses after a booster dose regime was conducted on day 28 post-injection. In almost all immunological assays, BoHV-4-tgDΔTK induced as high an immune response as pC-tgD. In both vaccine constructs, neutralizing antibodies were a significant determining factor in protection against BoHV-1, even after the first injection. We conclude that a BoHV-4-based viral vector offers an effective immunization strategy as an alternative to DNA-based immunization platforms, at least to combat BoHV-1.

Mitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

Background: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. Objective: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. Methods: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. Results: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18–55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. Conclusion: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

The blood and immune system of coronavirus disease 2019 (COVID-19) infected patients are dysfunctional, and numerous studies have been conducted to resolve their characteristics and pathogenic mechanisms. Nevertheless, the variations of immune responses along with disease severity have not been comprehensively documented. Here, we profiled the single-cell transcriptomes of 96,313 peripheral blood mononuclear cells (PBMCs) derived from 12 COVID-19 patients (including four moderate, four severe and four critical cases) and three healthy donors. We showed that proliferative CD8 effector T cells with declined immune functions and cytotoxicity accumulated in the critical stage. By contrast, the quantity of natural killer (NK) cells was significantly reduced, while they exhibited enhanced immune activities. Notably, a gradually attenuated responseto COVID-19 along with disease severity was observed in monocytes, in terms of cellular composition, transcriptional discrepancy and transcription factor regulatory network. Furthermore, we identified immune cell-type dependent cytokine signatures distinguishing the severity of COVID-19 patients. In addition, cell interactions between CD8 effector T/NK cells and monocytes mediated by inflammatory cytokines were enhanced in moderate and severe stages, but weakened in critical cases. Collectively, our work uncovers the cellular and molecular players underlying the disordered and heterogeneous immune responses associated with COVID-19 severity, which could provide valuable insights for the treatment of critical COVID-19 patients. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s11427-020-1880-y and is accessible for authorized users.

Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.

To study the effect of IL-5 on the immune response and lung injury in rats with sepsis. We constructed a rat model of sepsis by cecal ligation and puncture (CLP). The rats were randomly divided into the control group, the sham group, the CLP group and the IL-5 group, with 6 rats in each group. With the induction of CLP, the lung tissue of rats was severely injured, and the water content of lung tissue was significantly increased. Moreover, the ratio of CD4+/CD8+ was significantly decreased and Th1/Th2 was significantly increased in the peripheral blood. The content of IL-6, TNF-α, and HMGB1 was found to be increased in the CLP group. However, with the injection of IL-5, the degree of lung tissue injury in CLP rats was alleviated and the water content of lung tissue was significantly reduced. The ratio of CD4+/CD8+ was increased and Th1/Th2 was significantly down-regulated in the peripheral blood and the levels of IL-6, TNF-α, and HMGB1 in serum were significantly decreased. In conclusion, IL-5 can alleviate lung injury by regulating the immune response and inhibiting the systemic inflammatory response induced by sepsis., Graphical abstract

Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervoussystem (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiplesclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS. Refereed/Peer-reviewed

The immune system with its numerous and complex interactions helps to protect the host from pathogenic microorganisms, and enables cleaning of damaged tissues. It is also associated with constant “monitoring” of the appearance of malignant cells and their elimination that can occur in the human body. Such a role depends on many factors including adequate intake of nutrients, including vitamins. The effect of vitamin supplementation on the modulation of the immune response has always been the focus of numerous studies. Vitamins A and D have been shown to have the greatest immune-modulatory effect. In this review, we discuss and consider the possible roles of vitamins A and D on the immune response through innate and adaptive immune cells, with special focus on the cell population recently characterized as innate lymphoid cells. Recent literature data indicate that vitamin A and its metabolites modulate the balance between Th1 and Th2 immunity. In addition, vitamin D expresses protective effects on the innate immune system and inhibitory effects on adaptive immunity.

Background Muscle-invasive bladder cancer (MIBC) patients are subject to unfavorable treatment options and a high recurrence rate. The status of TP53 mutations played an essential role in the progression and the prognosis of MIBC. The present study proposed to investigate the association between TP53 mutations and immunophenotype in MIBC. Results We established an immune prognostic model (IPM) ground on the immune-associated genes derived from variation analysis between wild-type TP53 and mutated TP53 TCGA-MIBC patients, and validated in another cohort from GEO database. Based on IPM, we divided MIBC patients into low and high risk subgroups. The high risk MIBC patients had higher proportions of macrophages M1, and lower proportions of T cells regulatory (Tregs) and activated dendritic cells than the low risk MIBC patients. Moreover, the expression of immune checkpoints genes (PD1, CTLA4, LAG3, HAVCR2 and TIGIT) was higher in the high risk patients than the low risk patients. In clinical application, IPM exhibited better survival prediction than conventional clinical characteristics. Conclusions Our investigation presented practical prognostic significance for MIBC patients and displayed the overarching landscape of the immune response in the MIBC microenvironment. Methods Data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) analysis between the TP53 mutated and wild-type MIBC patients was conducted. The CIBERSORT algorithm was performed to evaluate the proportion of immune cell types. Gene expression profiles from the TCGA and GEO were used as training and testing cohorts to build and validate an immune-related prognostic model (IPM). Genes in the IPM model were first screened by univariate Cox analysis, then filtered by the least absolute shrinkage and selection operator (LASSO) Cox regression. A nomogram was finally established and evaluated by combining both the IPM and other clinical factors.

Physical frailty’s impact on hemagglutination inhibition antibody titers (HAI) and peripheral blood mononuclear cell (PBMC) transcriptional responses after influenza vaccination is unclear. Physical frailty was assessed using the 5-item Fried frailty phenotype in 168 community- and assisted-living adults ≥55 years of age during an observational study. Blood was drawn before, 3, 7, and 28 days post-vaccination with the 2017-2018 inactivated influenza vaccine. HAI response to the A/H1N1 strain was measured at Days 0 and 28 using seropositivity, seroconversion, log2 HAI titers, and fold-rise in log2 HAI titers. RNA sequencing of PBMCs from Days 0, 3 and 7 was measured in 28 participants and compared using pathway analyses. Frailty was not significantly associated with any HAI outcome in multivariable models. Compared with non-frail participants, frail participants expressed decreased cell proliferation, metabolism, antibody production, and interferon signaling genes. Conversely, frail participants showed elevated gene expression in IL-8 signaling, T-cell exhaustion, and oxidative stress pathways compared with non-frail participants. These results suggest that reduced effectiveness of influenza vaccine among older, frail individuals may be attributed to immunosenescence-related changes in PBMCs that are not reflected in antibody levels.

Chemotherapy resistance eventually develops in patients with gastric cancer (GC). Intra-tumoral heterogeneity (ITH) refers to the intercellular genetic variations and phenotypic diversity that affect responses to drug therapy. We measured ITH using mutant-allele tumor heterogeneity (MATH) derived from whole-exome sequencing data of patients with GC in The Cancer Genome Atlas (TCGA) database. The study included 385 patients from the TCGA database with available data regarding gastrectomy, survival, and whole-exome sequencing. Further analysis was performed in 171 GC patients with available data regarding adjuvant chemotherapy. Multiple factor analysis showed that MATH was an independent predictor of OS (hazard ratio [HR], 1.432; 95% confidence interval [CI], 1.073–1.913; P = 0.015) in patients with GC. Moreover, MATH was also an independent predictor of OS among the 171 GC patients who received adjuvant chemotherapy (HR, 2.016; 95% CI, 1.236–3.289; P = 0.005). Pathway enrichment and immune cell analyses revealed significantly higher infiltration by 20 types of immune cells in the low/intermediate group, compared to the group with high MATH scores. In conclusion, low/intermediate MATH scores predicted longer OS, when compared to those with high MATH scores. The immune response was obviously upregulated in patients with GC and low/intermediate MATH scores.

We present an integrated analysis of urine and serum proteomics and clinical measurements in asymptomatic, mild/moderate, severe and convalescent cases of COVID-19. We identify the pattern of immune response during COVID-19 infection. The immune response is activated in asymptomatic infection, but is dysregulated in mild and severe COVID-19 patients. Our data suggest that the turning point depends on the function of myeloid cells and neutrophils. In addition, immune defects persist into the recovery stage, until 12 months after diagnosis. Moreover, disorders of cholesterol metabolism span the entire progression of the disease, starting from asymptomatic infection and lasting to recovery. Our data suggest that prolonged dysregulation of the immune response and cholesterol metabolism might be the pivotal causative agent of other potential sequelae. Our study provides a comprehensive understanding of COVID-19 immunopathogenesis, which is instructive for the development of early intervention strategies to ameliorate complex disease sequelae.

Background The viral persistence in patients with Coronavirus Disease 2019 (COVID-19) remains to be investigated. Methods We investigated the viral loads, therapies, clinical features, and immune responses in a 70-year patient tested positive for SARS-CoV-2 for 3 months. Findings The patient exhibited the highest prevalence of abnormal indices of clinical features and immune responses at the first admission, including fever (38.3 ℃), decreased lymphocytes (0.83 × 109/L) and serum potassium (3.1 mmol/L), as well as elevated serum creatinine (115 µmol/L), urea (8.6 mmol/L), and C-reactive protein (80 mg/L). By contrast, at the second and the third admission, these indices were all normal. Through three admissions, IL-2 increased from 0.14 pg/mL, 0.69 pg/mL, to 0.91 pg/mL, while IL-6 decreased from 11.78 pg/mL, 1.52 pg/mL, to 0.69 pg/mL, so did IL-10 from 5.13 pg/mL, 1.85 pg/mL, to 1.75 pg/mL. The steady declining trend was also found in TNF-α (1.49, 1.15, and 0.85 pg/mL) and IFN-γ (0.64, 0.42, and 0.27 pg/mL). The threshold cycle values of RT-PCR were 26.1, 30.5, and 23.5 for ORFlab gene, and 26.2, 30.6, and 22.7 for N gene, showing the patient had higher viral loads at the first and the third admission than during the middle term of the disease. The patient also showed substantially improved acute exudative lesions on the chest CT scanning images. Conclusions The patient displayed declining immune responses in spite of the viral shedding for 3 months. We inferred the declining immune responses might result from the segregation of the virus from the immune system.

Since therapeutic strategies are limited in gliomas, new molecules or biomarkers are essential for diagnosis and therapy. Here, we investigated expression of protein disulfide isomerase family A member 3 (PDIA3) in gliomas to evaluate its potential as a promising immune target or biomarker. Transcriptome level, genomic profiles and its association with clinical practice from TCGA and CGGA databases were analyzed. All statistical analyses were performed using R project. In gliomas with high PDIA3 expression, somatic mutations showed the correlation with loss of PTEN and amplification of EGFR; meanwhile, in PDIA3 low gliomas, mutations in isocitrate dehydrogenase (IDH) took 80%. Moreover, PDIA3 was found to positively correlate with ESTIMATE scores and diverse infiltrating immune and stromal cell types localizing in tumor microenvironment. PDIA3 was found to be highly correlated with macrophage and T cells based on single cell sequencing. Additionally, PDIA3 was also involved in suppression of anti-tumor immunity via multiple immune regulatory processes. Finally, PDIA3 was observed to correlate with other immune checkpoint inhibitors and associated with inflammation. Our findings identified the significance of PDIA3 in the process of gliomas and demonstrated the potential of PDIA3 as a molecular target in prognosis and immune related treatment of gliomas.

Avian leukosis virus (ALV) is oncogenic retrovirus that not only causes immunosuppression but also enhances the host's susceptibility to secondary infection. Exosomes play vital role in the signal transduction cascades that occur in response to viral infection. We want to explore the function of exosomes in the spread of ALV and the body's subsequent immunological response. RNA-sequencing and the isobaric tags for relative and absolute quantitation (iTRAQ) method were used to detect differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in exosomes secreted by macrophage cells in response to injection with ALV subgroup J (ALV-J). RNA-sequencing identified 513 DEGs in infected cells, with specific differential regulation in mRNA involved in tight junction signaling, TNF signaling, salmonella infection response, and immune response, among other important cellular processes. Differential regulation was observed in 843 lncRNAs, with particular enrichment in those lncRNA targets involved in Rap1 signaling, HTLV-I infection, tight junction signaling, and other signaling pathways. A total of 50 DEPs were identified in the infected cells by iTRAQ. The proteins enriched are involved in immune response, antigen processing, the formation of both MHC protein and myosin complexes, and transport. Combined analysis of the transcriptome and proteome revealed that there were 337 correlations between RNA and protein enrichment, five of which were significant. Pathways that were enriched on both the RNA and protein levels were involved in pathways in cancer, PI3K-Akt signaling pathway, Endocytosis, Epstein-Barr virus infection. These data show that exosomes are transmitters of intercellular signaling in response to viral infection. Exosomes can carry both viral nucleic acids and proteins, making it possible for exosomes to be involved in the viral infection of other cells and the transmission of immune signals between cells. Our sequencing results confirme previous studies on exosomes and further find exosomes may cause immunosuppression and immune tolerance.

Background: The clinical benefit of immune response is largely unknown. We systematically explored the correlation of immune response with patient outcome in human cancers. Results: The global immune gene signature was primarily located on the plasma membrane with a high gene density at 6p21 and 1q23-1q24. Immune responses varied with a wide range in human cancers. A total of 11 cancer types exhibited significant correlation of immune response with overall survival. Higher immune response was significantly associated with longer overall survival in 7 types and with shorter overall survival in 4 types. In addition, 11 cancer types exhibited significant correlation of immune response with progression-free interval. Higher immune response was significantly associated with longer progression-free interval in 7 types and with shorter progression-free interval in 4 types. Methods: The Ingenuity Knowledge Base and human genome assembly GRCh38 were used to annotate the immune gene signature by cellular components and genomic coordinates, respectively. We devised an mRNA-based metric of pre-existing immune conditions by using the gene signature, and calculated the metric for 10,062 The Cancer Genome Atlas tumor samples across 32 different cancer types. The Kaplan-Meier method was used to evaluate the overall survival and progression-free interval differences between dichotomic groups stratified by the median metric for each cancer type. Conclusions: Immune responses have different impacts on patient outcome in different human cancers. Prospective verification is needed before the findings can be applied for clinical trial development.

This report describes efforts to understand the immune mechanism of action that led to a complete response in a patient with progressive, refractory, metastatic melanoma after treatment with a therapeutic vaccine consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from cells that were self-renewing in cell culture. Her histocompatibility type proved to be HLA B27 with extensive mutations in the HLA-A locus. Exomic analysis of proliferating tumor cells revealed more than 2800 non-synonymous mutations compared to her leukocytes. Histology of resected tumor lesions showed no evidence of an existing or suppressed immune response. In in vitro mixed cell cultures, DC loaded with ATA induced increased IL-22 expression, and a four-fold increase in CD8 + T lymphocytes. Cryopreserved blood samples obtained at week-0, 1 week before the first of three-weekly vaccine injections, and at week-4, 1 week after the third dose, were analyzed by protein array and compared for 110 different serum markers. At baseline, she had marked elevations of amyloid A, IL-12p40, IL21, IL-22, IL-10, IL-16, GROa, TNF-alpha, IL-3, and IL-2, and a lesser elevation of IL-15. One week after 3 weekly vaccinations she had a further 80% increase in amyloid A, a further 66% increase in IL-22, a 92% decrease in IL12p40, a 45% decrease in TGF-β and 26% decrease in IL-10. The data suggested that by 3 weeks after the first DCV injection, vaccine-induced changes in this particular patient were most consistent with enhanced innate and Th1 immune responses rather than Th2 or Th17.

In this study, erianin was found to reduce the viability of cancer cells, inhibit their proliferation and migration, induce G2/M phase arrest, enhance cancer cell apoptosis, promote an increase in levels of intracellular reactive oxygen species and a decrease in mitochondrial membrane potential, and regulate the expression levels of anti- and pro-apoptosis-related proteins in HepG2 and SMMC-7721 cells. Erianin inhibited tumor growth in HepG2- and SMMC-7721-xenograft tumor nude mouse models, reduced the expression levels of anti-apoptosis proteins and enhanced the expression levels of pro-apoptosis proteins in tumor tissues. Erianin inhibited tumor growth in immunosuppressed BALB/c mice bearing heterotopic tumors. Among 111 types of cytokines detected in proteome profiling of tumor tissues, erianin substantially influenced levels of 38 types of cytokines in HepG2-xenografted tumors and of 15 types of cytokines in SMMC-7721-xenografted tumors, most of which are related to immune functions. Erianin strongly affected the serum levels of cytokines, and regulated the activation of nuclear factor-kappa B (NF-κB), and the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins in spleen. The anti-liver cancer properties of erianin were found to be related mostly to its modulation of oxidative stress-mediated mitochondrial apoptosis and immune response.

// Yuexin Liu 1 1 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Yuexin Liu, email: yliu8@mdanderson.org Keywords: clinicopathological characteristics; immune response; immunogenicity; cancer Received: August 01, 2019 Accepted: September 24, 2019 Published: October 08, 2019 ABSTRACT Background: The clinicopathologic association of tumor immune response is largely unknown. We systematically investigated this matter in human cancers. Results: Different cancer types exhibited distinct immune gene profiling. Four cancer types exhibited a significant and positive correlation of immune response with patient age. Significant but inconsistent correlation of immune response was observed with gender, surgical stage, and TNM stage in a small number of cancer types. In contrast, the histological grade appears to have much stronger and more consistent association with immune response as compared to the other clinicopathologic factors. Specifically, patients with high grade had significantly higher immune responses than those with low grade in 5 out of 12 analyzed cancer types. In addition, both histological and molecular classifications had a significant and strong association with tumor immune response. Methods: t-distributed stochastic neighbor embedding was used to assess similarity of immune gene profiling in human cancers. The Mann-Whitney or Kruskal-Wallis test was, respectively, used to compare the tumor immune response in two or more groups that were stratified by patient clinicopathological characteristics, such as gender, grade, stage (including surgical and TNM stage), histology, and molecular subtypes. Spearman correlation with student’s t -test was used to examine the association of patient age with immune response. Multiple tests with the Benjamini-Hochberg correction also were performed. Conclusions: Tumor grade should be taken into account in selection of patient candidates for immunotherapy. Prospective verification is needed before use of the findings for clinical practice.

Recent studies demonstrated that CD155 plays an important role in anti-tumor immune responses. However, its role in glioma remains unclear. Here, we identify CD155 as a promising immune target in glioma. CD155 expression was significantly highly expressed in glioblastoma but not in normal brain tissue. Subsequent analysis based on genetic and clinical data from 1173 glioma patients in Rembrandt and TCGA dataset suggested that CD155 related genes of immune response were mainly positively correlated with CD155 expression. CD155 expression was positively correlated with immune-related metagenes STAT1, HCK, LCK, and MHC I but negatively associated with IgG. CD155 expression was positively correlated with biomarker gene expression of infiltrating immune cells, suggested that high CD155 expression in gliomas tend to have more infiltrating immune cells compared with gliomas with low CD155 expression. Pearson correlation analysis showed that CD155 is associated with CD96, CD226, Nectin4, PD-L1, B7-H2, NR2F6 and GITR, implying the potential synergistic effects of these checkpoint proteins. These findings implied that CD155 is a promising immunotherapy target, combined with existing immune checkpoint blockade therapies for glioma.

It focused on the antiviral immune regulation of biofilm-localized protein kinase Dbf2p-related kinase 1 (NDR1) in viral pneumonia. Mouse alveolar monocyte RAW264.7 was used as blank control, and viral pneumonia cell model was prepared by infecting cells with respiratory syncytial virus (RSV). NDR1 overexpression vector and siRNA interference sequences were synthesized, and overexpression/silence NDR1 cell model was fabricated. About 50 ng/mL interleukin 17 (IL-17) was given to stimulate. Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription PCR (RT-qRCR), and Western blot were performed to detect cytokines and chemokines, mRNA of inflammatory factors, and signal molecule protein expression. Notably, RSV infection increased RSV-F mRNA in RAW264.7 cells and reduced NDR1 mRNA and protein. Secretion levels of IL-6, interferon β (IFN-β), chemokine (C-X-C motif) ligand 2 (CXCL2), and chemokine (C-C motif) ligand 2 (CCL20) increased in the model group versus blank control (P 0.05). In short, NDR1 regulated innate immune response to viral pneumonia induced by IL-17, which can be used as a new target for the treatment of IL-17-induced inflammatory response and autoimmune diseases.

Background: The SARS-CoV-2 pandemic currently prevails worldwide. To understand the immunological signature of SARS-CoV-2 infections and aid the search and evaluation of new treatment modalities and vaccines, comprehensive characterization of adaptive immune responses towards SARS-CoV-2 is needed.Methods: We included 203 recovered SARS-CoV-2 infected patients in Denmark between April 3rd and July 9th 2020, at least 14 days after COVID-19 symptom recovery. The participants had experienced a range of disease severities from asymptomatic to severe. We collected plasma, serum and PBMC's for analysis of SARS-CoV-2 specific antibody response by Meso Scale analysis including other coronavirus strains, ACE2 competition, IgA ELISA, pseudovirus neutralization capacity, and dextramer flow cytometry analysis of CD8+ T cells. The immunological outcomes were compared amongst severity groups within the cohort, and 10 pre-pandemic SARS-CoV-2 negative controls.Findings: We report broad serological profiles within the cohort, detecting antibody binding to other human coronaviruses. 202(>99%) participants had SARS-CoV-2 specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 193(95%) individuals. A significant positive correlation (r=0.7804) between spike-ACE2 blocking antibody titers and neutralization potency was observed. Further, SARS-CoV-2 specific CD8+ T-cell responses were clear and quantifiable in 95 of 106(90%) HLA-A2+ individuals.Interpretation: The viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+ T-cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of their disease severity.Funding: This study was supported by the Danish Ministry for Research and Education (grant# 0238-00001B) and The Danish Innovation Fund (grant# 0208-00018B)

Environmental stressors like pathogens and toxins may depress the animal immune system through invasion of the gastrointestinal tract (GIT) tract, where they may impair performance and production, as well as lead to increased mortality rates. Therefore, protection of the GIT tract and improving animal health are top priorities in animal production. Being natural-sourced materials, phytochemicals are potential feed additives possessing multiple functions, including: anti-inflammatory, anti-fungal, anti-viral and antioxidative properties. This paper focuses on immunity-related physiological parameters regulated by phytochemicals, such as carvacrol, cinnamaldehyde, curcumin, and thymol; many studies have proven that these phytochemicals can improve animal performance and production. On the molecular level, the impact of inflammatory gene expression on underlying mechanisms was also examined, as were the effects of environmental stimuli and phytochemicals in initiating nuclear factor kappa B and mitogen-activated protein kinases signaling pathways and improving health conditions.

Phytochemicals which exist in various plants and fungi are non-nutritive compounds that exert numerous beneficial bioactive actions for animals. In recent years following the restriction of antibiotics, phytochemicals have been regarded as a primal selection when dealing with the challenges during the producing process in the poultry industry. The selected fast-growing broiler breed was more fragile when confronting the stressors in their growing environments. The disruption of oxidative balance that impairs the production performance in birds may somehow be linked to the immune system since oxidative stress and inflammatory damage are multi-stage processes. This review firstly discusses the individual influence of oxidative stress and inflammation on the poultry industry. Next, studies related to the application of phytochemicals or botanical compounds with the significance of their antioxidant and immunomodulatory abilities are reviewed. Furthermore, we bring up nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor kappa B (NF-κB) for they are respectively the key transcription factors involved in oxidative stress and inflammation for elucidating the underlying signal transduction pathways. Finally, by the discussion about several reports using phytochemicals to regulate these transcription factors leading to the improvement of oxidative status, heme oxygenase-1 gene is found crucial for Nrf2-mediated NF-κB inhibition.

Background The comprehensive characterization and prognostic relevance of immune activation in endometrial cancer remain largely unknown. Results We systematically reported a subset of endometrioid-type endometrial cancer characterized by multifaceted immune features such as low tumor purity, high leukocyte percentage, and striking CD8 lymphocytic infiltration with anti-tumor efficacy along with marked upregulation of immunosuppressive gene markers. We also showed that genes whose expression was significantly correlated with better survival were significantly enriched in the immune-related signaling pathways, suggesting that tumor-infiltrating lymphocytes give rise to a favorable prognosis in endometrial cancer. Furthermore, we showed that immune cell recruitment in this subset of tumors is likely due to the transcriptional activation of the STAT1 signaling network. Methods We obtained the multi-dimensional genomic data from publicly available databases and correlated them with the four gene expression-based subtypes we recently identified in endometrial cancer. Upstream regulator analysis was used to identify the most significantly enriched transcription regulators and Ingenuity pathway analysis was applied to determine enrichment of signaling pathways in survival-associated genes. Gene set enrichment analysis was performed on the 200-gene T-cell tumor infiltration gene signature comparing Cluster IV with the other three clusters combined. All statistical tests were two-sided, and a P value of less than 0.05 is considered significant across all analyses performed. Conclusion This study helps to identify patients with immune activation who are likely to benefit from emerging immune checkpoint inhibitors.

With a broad range of hosts, Salmonella enterica serovar Typhimurium (S. Typhimurium) is the major cause of gastroenteritis in human beings and systemic disease in susceptible mice strains. However, different S. Typhimurium strains differ in regard to virulence and host adaptation. Here, C57BL/6 mice were infected, respectively, with different S. Typhimurium strains SL1344 (calf), CVCC541 (chicken) and CMCC50115 (mutton) to determine their virulence and host immune responses. It was found that mice were less susceptible to infection by S. Typhimurium CVCC541 and CMCC50115 strains, with lower lethality and decreased bacterial burden in liver and spleen. Besides, S. Typhimurium strains CVCC541 and CMCC50115 enhanced host innate immune responses by increased frequencies of macrophages and neutrophils 3 days after infection. But SL1344 strain evaded immune response by inducing apoptosis of macrophages. Moreover, CVCC541 could elicit adaptive immune responses of host 11 days after infection upon examination of the proliferation and activation of CD4+ T cells. In addition, 125 and 138 unique mutant coding genes, respectively, in S. Typhimurium strains CVCC541 and CMCC50115 and 78 shared mutant coding genes were annotated by genomic alignment to SL1344 genome and the signal pathways involving these genes were further analyzed. The acquired results indicate that different original S. Typhimurium strains show differential virulence and may induce diverse immune responses in the same host infected.

Streptococcus suis is a major porcine bacterial pathogen and emerging zoonotic agent. S. suis 5ʹ-nucleotidase is able to convert adenosine monophosphate to adenosine, resulting in inhibiting neutrophil functions in vitro and it is an important virulence factor. Here, we show that S. suis 5ʹ-nucleotidase not only enables producing 2ʹ-deoxyadenosine from 2ʹ-deoxyadenosine monophosphate by the enzymatic assay and reversed-phase high performance liquid chromatography (RP-HPLC) analysis in vitro, but also synthesizes both 2ʹ-deoxyadenosine and adenosine in mouse blood in vivo by RP-HPLC and liquid chromatography with tandem mass spectrometry analyses. Cellular cytotoxicity assay and Western blot analysis indicated that the production of 2ʹ-deoxyadenosine by 5ʹ-nucleotidase triggered the death of mouse macrophages RAW 264.7 in a caspase-3-dependent way. The in vivo infection experiment showed that 2ʹ-deoxyadenosine synthesized by 5ʹ-nucleotidase caused monocytopenia in mouse blood. The in vivo transcriptome analysis in mouse blood showed the inhibitory effect of 5ʹ-nucleotidase on neutrophil functions and immune responses probably mediated through the generation of adenosine. Taken together, these findings indicate that S. suis synthesizes 2ʹ-deoxyadenosine and adenosine by 5ʹ-nucleotidase to dampen host immune responses, which represents a new mechanism of S. suis pathogenesis.

Since universal vaccinations represents the most effective strategy to mitigate coronavirus disease 2019 (COVID-19), baseline assessment and post-vaccine monitoring of anti-SARS-CoV-2 neutralizing antibodies are essential to vaccination programs. Therefore, this study aimed to compare data of five commercial anti-SARS-CoV2 immunoassays after administration of an mRNA vaccine.Venous blood was collected from three healthcare workers, receiving a double (30 g) dose of BNT162b2 mRNA Covid-19 vaccine (Comirnaty, Pfizer), on the day of the first vaccine dose and then at fixed intervals for the following 2 months. Anti-SARS-CoV-2 neutralizing antibody response was assayed with Roche Total Ig anti-RBD (receptor binding domain), DiaSorin TrimericS IgG (spike trimer), Beckman Coulter IgG anti-RBD, SNIBE IgG anti-RBD and Technogenetics IgG anti-N/S1.A total number of 45 samples were drawn at the end of the 2-month study period. The Spearman's correlations of absolute anti-SARS-CoV-2 antibodies were always excellent (all p0.001), comprised between 0.967-0.994. Satisfactory results were also observed when absolute antiSARS-CoV-2 antibodies values of the five methods were compared with the mean consensus value, with correlations always higher than 0.979 (all p0.001). The agreement of anti-SARS-CoV-2 antibodies positivity versus the consensus median positivity ranged between 0.764 and 1.000 (always p0.001), but become always0.900 after readjustment of one assay cutoff.All the immunoassays evaluated in this study appear suitable for monitoring anti-SARS-CoV-2 neutralizing antibodies response in subjects undergoing mRNA COVID-19 vaccination.Pošto univerzalna vakcinacija pretstavlja najefikasniju strategiju za zaustavljanje koronavirus oboljenja 2019 (COVID-19) veoma je važno praćenje nakon vakcinacije anti-SARS-CoV-2 antitela koja su va`na za programe vakcinacije. Iz tog razloga ovo proučavanje je imalo za cilj da poredi podatke pet komercijalnih anti-SARS-CoV-2 imunodređivanja nakon davanja mRNA vakcine.Uzeta je venska krv od tri zdravstvena radnika koja su primila duplu dozu (30 g) BNT-162b2 mRNA Covid-19 vakcine (Comirnaty, Pfizer) odmah nakon davanja prve doze vakcine a zatim u fiksiranim intervalima u roku od sledeća 2 meseca. Anti-SARS-CoV-2 neutrališuća antitela su određivana sa Roche Total Ig anti-RBD (receptor vezujući domen), DiaSorin TrimericS IgG (spike trimer), Beckman Coulter IgG anti-RBD, SNIBE IgG anti-RBD i Technogenetics IgG antiN/S1.Nakon 2 meseca uzeto je 45 uzoraka. Spearma - nova korelacija apsolutnih anti-SARS-CoV-2 antitela bila je uvek odlična (svi p0,001) sa obuhvatom između 0,967-0,994. Zadovoljavajući rezultati su dobijeni između vrednosti apsolutnih anti-SARS-CoV-2 antitela dobijenih sa svih pet metoda kad su upoređivane sa konsenzus vrednostima i korelacijom koja je bila veća od 0,979 (svi p0,001). Slaganje pozitivnosti anti-SARS-CoV-2 antitela prema konsenzus srednjoj pozitivnosti koja se kretala između 0,764 i 1,000 (uvek p0,001), bila je uvek0,900 nakon podešavanja cutoff vrednosti za jedno određivanje.Sva imunodređivanja koja su procenjivana u ovom izučavanju su pogodna za praćenje anti-SARS-CoV-2 netralizirajućih antitela koja nastaju kod osoba koja su bila vakcinisana sa mRNA COVID-19 vakcinom.

Most studies on immune response after coronavirus disease 2019 (COVID-19) vaccination focused on serum IgG antibodies and cell-mediated immunity, discounting the role of anti-SARS-CoV-2 neutralizing IgA antibodies in preventing viral infection. This study was aimed to quantify serum IgG and IgA neutralizing antibodies after mRNA COVID-19 vaccination in baseline SARS-CoV-2 seronegative healthcare workers.The study population consisted of 181 SARSCoV-2 seronegative healthcare workers (median age 42 years, 59.7% women), receiving two doses of Pfizer COVID-19 vaccine BNT162b2 (Comirnaty). Serum samples were collected before receiving the first vaccine dose, 21 days (before the second vaccine dose) and 50 days afterwards. We then measured anti-spike trimeric IgG (Liaison XL, DiaSorin), anti-spike receptor binding domain (RBD) IgG (Access 2, Beckman Coulter) and anti-spike S1 subunit IgA (ELISA, Euroimmun). Results were presented as median and interquartile range (IQR).Vaccine administration elicited all anti-SARS-CoV2 antibodies measured. Thirty days after the second vaccine dose, 100% positivization occurred for anti-spike trimeric IgG and anti-spike RBD IgG, whilst 1.7% subjects remained anti-spike S1 IgA negative. The overall increase of antibodies level ratio over baseline after the second vaccine dose was 576.1 (IQR, 360.7-867.8) for anti-spike trimeric IgG, 1426.0 (IQR, 742.0-2698.6) for anti-spike RBD IgG, and 20.2 (IQR, 12.5-32.1) for anti-spike S1 IgA. Significant inverse association was found between age and overall increase of anti-spike trimeric IgG (r=-0.24; p=0.001) and anti-spike S1 IgA (r=-0.16; p=0.028), but not with anti-spike RBD IgG (r=-0.05; p=0.497).mRNA COVID-19 vaccination elicits sustained serum levels of anti-spike trimeric IgG and anti-spike RBD IgG, while also modestly but significantly increasing those of anti-spike S1 IgA.Većina studija imunog odgovora nakon oboljenja korona virusom (COVID-19) i vakcinacije zasniva se na serumskim IgG antitelima i ćelijski posredovanom imunitetu, ne vodeći računa o anti-SARS-CoV-2 neutralizujućim IgA antitelima i sprečavanju virusne infekcije. Ovo izučavanje ima za cilj da kvantifikuje serumski IgG i IgA neutralizujućih antitela nakon mRNA COVID-19 vakcinacije kod SARSCOV-2 seronegativnih zdravstvenih radnika.Populaciju za izučavanje činilo je 181 SARS-COV-2 seronegativna zdravstvena radnika (oko 42 godine starosti, 59,76% su bile `ene) koji su primili dve doze Pfizer COVID10 vakcinu BNT162b2 (Comirnaty). Uzorci seruma su uzeti pre prijema prve vakcine, 21 dan pre druge doze vakcine i 50 dana nakon druge doze vakcine. Mereni su anti-spike trimerik IgG (Liaison XL, DiaSorin), anti-spike receptor vezujući domen (RBD), IgG (Access 2, Beckman Cooulter) i antispike S1 subjedinica IgA (ELISA, Euroimmun). Rezultati su prikazani kako medijana i interkvartilna oblast (IQR).Vakcina je proizvela sva anti-SARS-CoV-2 antitela koja su merena. Trideset dana nakon davanja doze vakcine javila se 100% pozitivnost na anti-spike trimerni IGG i antispike RBS IgG, dok je 1,7% osoba bilo negativno na antispike S1 IgA. Ukupno povećanje nivoa antitela iznad bazične granice nakon druge vakcine bila je 576,1 (IQR, 360,7-867,8) za anti-spike trimerni IgG, 1426,0 (IQR, 742,0-2698,6) za anti-spike RBS IgG i 290,2 (IQR, 12,5-32,1) za anti-spike S1 IgA. Značajno obrnuta povezanost je nađena između godina i i ukupnog povećanja anti-spike trimernog IgG (r = -0,24; p = 0,001) i anti-spike S1 IgA (r = 0,16; p = -0,028) ali ne i sa anti-spike RBD IgG (r= 0,05; p = 0,497).mRNA COVID-19 vakcinacija dovodi do povećanja nivoa u serumu anti-spike trimernog IgA i RBD IgG, kao i do značajnog povećanja u serumu anti-spike S1 IgA.

As one of the 10 most common cancers in men, the incidence of renal cell carcinoma (RCC) has been increasing in recent years. Clear cell renal cell carcinoma (ccRCC) is the most common pathological type of RCC, counting for 80%-90% of cases. Immunotherapy is becoming increasingly important in the treatment of advanced RCC. Tumor mutation burden (TMB) is a potent marker for predicting the response to immune checkpoint blockade (ICB) treatment. Here, we analyzed somatic mutation data for ccRCC from The Cancer Genome Atlas datasets. We found that the frequently mutated gene SYNE1 is associated with higher TMBs and with a poor clinical prognosis. To further investigate the relationship between SYNE1 mutation and the immune system, we used Gene Set Enrichment Analysis and the CIBERSORT algorithm. They showed that SYNE1 mutations correlate with immune system pathways and immune cell tumor infiltration. We also found that SYNE1 mutation correlated with a better response to ICB therapy. Thus, mutation of SYNE1 correlates with a higher TMB and a poorer outcome in ccRCC, but may mediate better responses to ICB therapy.

Background OGN could modify tissue inflammation and immune response via local and circulating innate immune cells, which was suggestive of a reciprocal relationship between OGN and T cell infiltration in cancer. Hence, we aim to measure the OGN expression patterns and immune cells response in colorectal cancer(CRC). Methods This study enrolled three independent sets of patients from TCGA and the Fudan University Shanghai Cancer Center(FUSCC). The effect of OGN on T cell infiltration and the mechanism were examined in vitro and in vivo. Findings Tumor OGN expression levels were positively associated with CD3, CD8, and PTPRC expressions in the training and testing sets from TCGA, respectively. In validation set from FUSCC, OGN expression level also paralleled positively with CD8+ cell density in colorectal cancer tissue (p, Highlights • OGN is positively associated with T cell density in CRC • OGN inhibited the activation of HIF-1α, then significantly impeded the expression of VEGF.

Purpose We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM). Patients and Methods Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics. Results Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a ‘partial’ combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p, Highlights • Cytokine combinations of IL-4/5/6 or IFN-γ/TNF-α/IL-17A may predict survival in patients with GBM. • IL-2/15/21-amplified survivin peptide-specific T-cell responses may independently predict survival among patients with GBM. • Large-scale clinical studies to validate these readouts as biomarkers of survival in GBM are warranted.

A wheat LLM-domain-containing B-GATA transcription factor positively regulates the host immune response to the important pathogen Rhizoctonia cerealis., Wheat (Triticum aestivum) is essential for global food security. Rhizoctonia cerealis is the causal pathogen of sharp eyespot, an important disease of wheat. GATA proteins in model plants have been implicated in growth and development; however, little is known about their roles in immunity. Here, we report a defence role for a wheat LLM-domain-containing B-GATA transcription factor, TaGATA1, against R. cerealis infection and explore the underlying mechanism. Through transcriptomic analysis, TaGATA1 was identified to be more highly expressed in resistant wheat genotypes than in susceptible wheat genotypes. TaGATA1 was located on chromosome 3B and had two homoeologous genes on chromosomes 3A and 3D. TaGATA1 was found to be localized in the nucleus, possessed transcriptional activation activity, and bound to GATA-core cis-elements. TaGATA1 overexpression significantly enhanced resistance of transgenic wheat to R. cerealis, whereas silencing of TaGATA1 suppressed the resistance. Quantitative reverse transcription–PCR and ChIP–qPCR results indicated that TaGATA1 directly bound to and activated certain defence genes in host immune response to R. cerealis. Collectively, TaGATA1 positively regulates immune responses to R. cerealis through activating expression of defence genes in wheat. This study reveals a new function of plant GATAs in immunity and provides a candidate gene for improving crop resistance to R. cerealis.

Reactive oxygen species (ROS) modulator 1 (Romo1) is a mitochondrial membrane protein that is essential for the regulation of mitochondrial ROS production and redox sensing. Although the physiological functions of Romo1 have been studied for the past few years, the role of Romo1 in cancer remained unclear. In this study, we found that the high expression of Romo1 is associated with the poor prognosis of glioblastoma patients. Further study revealed that Romo1 is highly expressed in macrophages, indicating that the overexpression of Romo1 may participate in the function of macrophages and contribute to the progression of glioblastoma. Through the glioblastoma mouse model, we found that the overexpression of Romo1 in bone marrow cells significantly inhibited the immune response within tumor microenvironment, and that the overexpression of Romo1 resulted in the M2 polarization of bone marrow derived macrophages (BMDMs) through mTORC1 signaling pathway. In addition, the inhibition of Romo1 combining with anti-PD-1 immunotherapy significantly improved the survival outcome of glioblastoma in mouse model. Collectively, our study highlights the important role of Romo1 in immune response especially the function of macrophages, and implicates it as a potential target of immunotherapy for glioblastoma.

The composition of the intestinal microbiota is related to the health and immune function of the host. Administration of antibiotics affects the composition of the intestinal microbiota. However, the effects of immune function on the composition of the intestinal microbiota are still unclear. In this study, we investigated the lymphocyte composition and determined the relationships between lymphocyte function and the intestinal microbiota following antibiotic treatment in mice. To change the composition of the intestinal microbiota, mice were treated with or without antibiotics. Analysis of intestinal microbiota was performed by metagenomic analysis targeting 16S rRNA. Lymphocyte subsets of splenocytes were measured by flow cytometry. For functional analysis of T cells, splenocytes were stimulated with concanavalin (Con A), and cytokine gene expression was measured by real-time polymerase chain reaction. Firmicutes were predominant in the control group, whereas Bacteroidetes predominated in the antibiotic-treated group, as determined by metagenomic analysis. The diversity of the microbiota decreased in the antibiotic-treated group. Analysis of lymphocyte subsets showed that CD3(+) cells decreased, whereas CD19(+) cells increased in the antibiotic-treated group. All cytokine genes in splenocytes treated with Con A were downregulated in the antibiotic-treated group; in particular, genes encoding interferon-gamma, interleukin (IL)-6, and IL-13 significantly decreased. Taken together, these results revealed that changes in the composition of the intestinal microbiota by antibiotic treatment influenced the population of lymphocytes in splenocytes and affected the immune response.

Cryoablation is moderately effective against prostate cancer. Of note, the off-target or enlarged therapeutic effect after cryoablation is reported in routine clinical practice. To uncover it, we constructed a bilateral inguinal transplantation model of prostate cancer. All the mice were randomly subdivided into three groups: Group A (Control group), Group B (Surgery group), and Group C (Cryoablation group). All the procedures in three groups were conducted only for tumors in the target region (right groin). The tumors in untargeted region (left groin) received no treatment. We measured the growth of untargeted tumors and lung metastasis rate, and then explored the changes in a series of immune cells and danger signals. First, our results revealed the protective effect of cryoablation treatment against the abscopal tumor. The possible mechanism was mediated by an increase in the number of CD4+ T cells, CD8+ T cells, ratio T helper 1 (Th1)/Th2, the killing activity of cytotoxic T lymphocytes and NK cells. Hsp70 may be involved in the modulation of the immune response. The combination of weakened Ki67 activity and activated immune response delayed spectator tumor growth, decreased the pulmonary metastasis rate, and prolonged animal survival, with an inducible abscopal effect.

CD147, encoded by BSG, is a highly glycosylated transmembrane protein that belongs to the immunological superfamily and expressed on the surface of many types of cancer cells. While CD147 is best known as a potent inducer of extracellular matrix metalloproteinases, it can also function as a key mediator of inflammatory and immune responses. To systematically elucidate the function of CD147 in cancer cells, we performed an analysis of genome-wide profiling across the Cancer Cell Line Encyclopedia (CCLE). We showed that CD147 mRNA expression was much higher than that of most other genes in cancer cell lines. CD147 varied widely across these cell lines, with the highest levels in the ovary (COLO704) and stomach (SNU668), intermediate levels in the lung (RERFLCKJ, NCIH596 and NCIH1651) and lowest levels in hematopoietic and lymphoid tissue (UT7, HEL9217, HEL and MHHCALL3) and the kidney (A704 and SLR20). Genome-wide analyses showed that CD147 expression was significantly negatively correlated with immune-related genes. Our findings implicated CD147 as a novel regulator of immune-related genes and suggest its important role as a master regulator of immune-related responses in cancer cell lines. We also found a high correlation between the expression of CD147 and FOXC1, and proved that CD147 was a direct transcriptional target of FOXC1. Our findings demonstrate that FOXC1 is a novel regulator of CD147 and confirms its role as a master regulator of the immune response.

Although there is ample evidence that the chemotherapeutic drugs trigger an immune response, the efficient tumor rejection or regression is not guaranteed probably due to the massive immunosuppression within the tumor microenvironment. Thus, a rational delivery platform that overcomes immunosuppression is needed to maximally achieve both cytotoxic and immune-modulatory functions of chemotherapeutics. Accumulating evidence suggests that platinum-based drugs might be suitable for this application. Methods: The dendrigraft polylysine (DGL) with its uniform size and multifunctional groups was employed as the polymeric core and conjugated with platinum-based compounds as therapeutics and WKYMVm peptide (Wpep) as a targeting ligand to construct the novel delivery platform Wpep-DGL/Pt. A series of in vitro and in vivo analyses, including physical and chemical characterizations, targeting property, biosafety, and antitumor efficacy of Wpep-DGL/Pt were systematically carried out. Results: Wpep-DGL/Pt showed potent antitumor efficacy in MDA-MB-231 cells tumor-bearing nude mice with a deficient immune system, demonstrating targeted delivery of chemotherapeutics and the resultant cytotoxicity. Furthermore, in immunocompetent mice bearing 4T1 cells tumors, Wpep-DGL/Pt activated immune cells and induced cell death proving their dual function of chemotherapeutic and immunomodulatory efficacy. Conclusion: This work represents a novel approach for cancer immunotherapy by integrating nanotechnology and platinum-based therapeutics which not only efficiently exerts the chemotherapeutic cytotoxic effect on tumor cell but also restores immune response of immunological cells within the tumor microenvironment.

// Yu-Jie Wang 1,2,* , Lin Li 1,4,* , Wei-Juan Song 3,* , Yan-Jun Zhou 1 , Meng-Da Cao 1 , Xiang-Rong Zuo 1,2 and Ji-Fu Wei 1 1 Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 2 Department of Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 3 Department of Clinical Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 4 Department of Emergency Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China * These authors have contributed equally to this article Correspondence to: Xiang-Rong Zuo, email: // Ji-Fu Wei, email: // Keywords : Can f 6, dog allergy, epitopes, allergenicity, Chinese children, Immunology and Microbiology Section, Immune response, Immunity Received : July 07, 2017 Accepted : September 20, 2017 Published : October 13, 2017 Abstract Dog allergy is common worldwide. However, the allergenicity of dog allergy is still unclear in China as well as in special group, such as children. In this study, we chose Can f 6, a major dog allergen which belongs to the lipocalin to study its allergenicity in Chinese dog allergic children. Can f 6 gene was subcloned into pET-28a vector and transformed into E. coli BL21 (DE3) cells for expression. The recombinant Can f 6 was purified by nickel affinity chromatography, identified by SDS-PAGE, and tested for its allergenicity by Western blot with sera and basophil activation test. Secondary structures, B cell epitopes and homology modeling of Can f 6 were predicted by using a series of bioinformatical approaches. And the verification of B cell epitopes was detected by ELISA. The recombinant allergen showed an explicit band with the molecular weight of 20 kDa by SDS-PAGE. Sera from 56.3 % (18/32) of dog-allergic children patients reacted with Can f 6. The induction of the expression of CD63 and CCR3 of dog allergic children in passively sensitized basophils was up to approximately 5.0 times higher than healthy subjects. The secondary structure of Can f 6 contains 3 α-helices, 9 β-sheets and random coils. Five B cell epitopes of Can f 6 were predicted and were confirmed successfully by ELISA. The results showed Can f 6 is a major allergen in Chinese children, which provides a basis for further study of Can f 6 in diagnosis and treatment of symptoms in children in China. The structural information of Can f 6 will help to form a foundation for the future design of vaccines and therapies for Can f 6 related allergies.

// Zhaoduan Liang 1 , Ye Tian 1 , Wenxuan Cai 1 , Zhiming Weng 3 , Yanyan Li 1 , Huanling Zhang 1,2 , Yifeng Bao 1 and Yi Li 1,3 1 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China 2 School of Life Sciences, University of Science and Technology of China, Hefei, China 3 XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd., Guangzhou, China Correspondence to: Yi Li, email: // Keywords : high affinity, programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1), soluble PD-L1, T cell, Immunology and Microbiology Section, Immune response, Immunity Received : August 15, 2017 Accepted : September 03, 2017 Published : October 10, 2017 Abstract The activated T cells can be suppressed by programed death-1 (PD-1) axis through low affinity interaction between PD-1 and PD-ligand 1 (PD-L1) in solution or on antigen presenting cells. In clinic, the concentration of soluble PD-L1 in peripheral blood negatively correlates with cancer prognosis. However, there is little information about the relation between the affinity of PD-1/PD-L1 interaction and the suppressive capacity of PD-1 axis. In this study, we analyzed inhibitory roles of high affinity soluble human PD-L1 (hPD-L1) variants, which were generated with directed molecular evolution. Resultant two clones L3C7-hPD-L1 and L3B3-hPD-L1 showed over 20 folds greater affinity than that of native hPD-L1. We found that L3B3-hPD-L1 and L3C7-hPD-L1 could compete with an anti-PD-1 antibody (EH12.1) for binding to hPD-1. More importantly, although native soluble hPD-L1 can induce suppressive effects on activated T cells, we found L3B3-hPD-L1 and L3C7-hPD-L1 attenuated the strength of PD-1 axis for suppressing the proliferation and interferon γ (IFN-γ) secretion of PBMC. In conclusion, our data provide direct evidence in which immune checkpoint receptor-ligand interactive strength can alter the the suppressive function, in particular, the suppressive capacity of PD-1 axis could be decreased with enhanced affinity of soluble PD-L1 and PD-1 interaction. Our study might provide a new direction for manipulating immune checkpoints.

// Consuelo Amantini 1,* , Valerio Farfariello 2,* , Claudio Cardinali 3,4 , Maria Beatrice Morelli 3,4 , Oliviero Marinelli 1 , Massimo Nabissi 3 , Matteo Santoni 3 , Laura Bonfili 1 , Valentina Cecarini 1 , Anna Maria Eleuteri 1 and Giorgio Santoni 3 1 School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy 2 University of Lille, INSERM U1003 - PHYCEL - Physiologie Cellulaire, Lille, France 3 School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy 4 Department of Molecular Medicine, Sapienza University, Rome, Italy * These authors have contributed equally to this work Correspondence to: Consuelo Amantini, email: // Keywords : ER stress, capsaicin, TRPV1, TRPV1 KO mice, autophagy, Immunology and Microbiology Section, Immune response, Immunity Received : July 28, 2017 Accepted : September 20, 2017 Published : October 11, 2017 Abstract Autophagy and the ubiquitin-proteasome system (UPS) control thymus cell homeostasis under resting and endoplasmic reticulum (ER) stress conditions. Several evidence support a cross-talk between UPS and autophagy; abrogation of UPS responses stimulates autophagy, and vice versa the inhibition of autophagy alters the UPS functions. Herein, we found that TRPV1 activation induces ER stress, proteasome dysfunction and autophagy in thymocytes by modulating the expression of UPR-related genes. The TRPV1-mediated autophagy prevents the UPR activation by inhibiting BiP, Grp94 and ERp57 chaperone protein expression. Thymocytes from TRPV1 KO mice display both autophagy and proteasome dysfunctions, resulting in increased apoptotic cells and reduced total DP thymocyte number. In addition, positive selection of thymocytes triggered by anti-TCRβ/CD2 Ab-mediated costimulation induces apoptosis in thymocytes from TRPV1 KO as compared with WT mice. Stimulation of TRPV1 KO thymocytes with anti-TCRβ/CD2 mAbs modulates the expression of CD4 antigen on purified DP thymocytes, with reduced number of mature, single positive (SP) CD4 and increased number of immature SP CD4 low and DP CD4 low CD8 + thymocytes, further supporting the intrinsic role of TRPV1 in T cell maturation. Finally, a reduction in CD8 + and CD4 + T cells is evidenced in the peripheral blood and spleen of TRPV1 KO, as compared with WT mice. Therapeutic strategy by restraining or stimulating the TRPV1 expression and functions in thymocytes might represent a new pharmacological tool in the regulation of different inflammatory T cell responses.

// Kyung-Ah Cho 1 , Minhwa Park 1 , Yu-Hee Kim 1 , Kyung-Ha Ryu 2 and So-Youn Woo 1 1 Department of Microbiology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea 2 Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul, Republic of Korea Correspondence to: So-Youn Woo, email: // Keywords : mesenchymal stem cells, osteoprotegerin, Th17 cells, osteoclasts, psoriasis, Immunology and Microbiology Section, Immune response, Immunity Received : February 20, 2017 Accepted : September 05, 2017 Published : September 28, 2017 Abstract Th17 cells play a critical role in several autoimmune diseases, including psoriasis and psoriatic arthritis (PsA). Psoriasis is a chronic inflammatory skin disease associated with systemic inflammation and comorbidities, such as PsA. PsA develops in nearly 70% of patients with psoriasis, and osteoclasts associated bone erosion is a hallmark of the disease. Thus far, the effect of Th17 cells on osteoclastogenesis via direct cell-to-cell interactions is less understood. In this study, we observed that Th17 cells directly promote osteoclast differentiation and maturation via expression of receptor activator of nuclear factor-κ β ligand (RANKL) in vitro . We investigated the impact of conditioned medium obtained from human palatine tonsil-derived mesenchymal stem cells (T-CM) on the interactions between osteoclasts and Th17 cells. T-CM effectively blunted the RANK-RANKL interaction between the osteoclast precursor cell line RAW 264.7 and Th17 cells via osteoprotegerin (OPG) activity. The frequency of tartrate-resistant acid phosphatase (TRAP)-positive cells in the bone marrow of an imiquimod (IMQ)-induced psoriasis mouse model was decreased following T-CM injection. Therefore, our data provide novel insight into the therapeutic potential of tonsil-derived mesenchymal stem cell-mediated therapy ( via OPG production) for the treatment of pathophysiologic processes induced by osteoclasts under chronic inflammatory conditions such as psoriasis.