Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 571
Filtrar
1.
Medicine (Baltimore) ; 99(25): e20617, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569190

RESUMO

BACKGROUND: Colorectal cancer (CRC) has been divided into 4 consensus molecular subtypes (CMSs), of which CMS4 has the mesenchymal identity and the highest relapse rate. Our goal is to develop a prognostic signature by integrating the immune system and mesenchymal modalities involved in CMS4. METHODS: The gene expression profiles collected from 5 public datasets were applied to this study, including 1280 samples totally. Network analysis was applied to integrate the mesenchymal modalities and immune signature to establish an immune-based prognostic signature for CRC (IPSCRC). RESULTS: We identified 6 immune genes as key factors of CMS4 and established the IPSCRC. The IPSCRC could significantly divide patients into high- and low- risk groups in terms of relapse-free survival (RFS) and overall survival (OS) and in discovery (RFS: P < .0001) and 4 independent validation sets (RFS range: P = .01 to <.0001; OS range: P = .02-.0004). After stage stratification, the IPSCRC could still distinguish poor prognosis patients in discovery (RFS: P = .04) and validation cohorts (RFS range: P = .04-.007) within stage II in terms of RFS. Further, in multivariate analysis, the IPSCRC remained an independent predictor of prognosis. Moreover, Macrophage M2 was significantly enriched in the high-risk group, while plasma cells enriched in the low-risk group. CONCLUSION: We propose an immune-based signature identified by network analysis, which is a promising prognostic biomarker and help for the selection of CRC patients who might benefit from more rigorous therapies. Further prospective studies are warranted to test and validate its efficiency for clinical application.


Assuntos
Neoplasias Colorretais/genética , Células-Tronco Mesenquimais/citologia , Transcriptoma/imunologia , Biomarcadores Tumorais/imunologia , Estudos de Coortes , Neoplasias Colorretais/classificação , Neoplasias Colorretais/imunologia , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia
2.
Cancer Immunol Immunother ; 69(9): 1881-1890, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32372138

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) has become the most frequent histologic type of lung cancer in the past several decades. Recent successes with immune checkpoint blockade therapy have demonstrated that the manipulation of the immune system is a very potent treatment for LUAD. This study aims to explore the role of immune-related genes in the development of LUAD and establish a signature that can predict overall survival for LUAD patients. METHODS: To identify the differential expression genes (DEGs) between normal and tumor tissues, we developed an analysis strategy to combine an independent-sample design and a paired-sample design using RNA-seq transcriptomic profiling data of The Cancer Genome Atlas LUAD samples. Further, we selected prognostic markers from DEGs and evaluated their prognostic value in a prediction model. RESULTS: We identified and validated PD1, PDL1 and CTLA4 genes as prognostic markers, which are well-known immune checkpoints, and revealed two new potential prognostic immune checkpoints for LUAD, HHLA2 (logFC = 2.55, FDR = 1.89 × 10-6) and VTCN1 (logFC = -2.86, FDR = 1.72 × 10-11). Furthermore, we identified an 18-gene LUAD prognostic biomarker panel and observed that the classified high-risk group presented a significantly shorter overall survival time (HR = 3.57, p value = 4.07 × 10-10). The prediction model was validated in five independent high-throughput gene expression datasets. CONCLUSIONS: The identified DEG features may serve as potential biomarkers for prognosis prediction of LUAD patients and immunotherapy. Based on that assumption, we identified a gene expression-based immune signature for lung adenocarcinoma prognosis.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Idoso , Biomarcadores Tumorais/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Prognóstico
3.
Cancer Immunol Immunother ; 69(9): 1905-1916, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32377818

RESUMO

Giant cell tumor of bone (GCTB) is a locally aggressive and rarely metastatic tumor, with a relatively unpredictable clinical course. A retrospective series of 46 GCTB and a control group of 24 aneurysmal bone cysts (ABC) were selected with the aim of investigating the PD-L1 expression levels and immune-related gene expression profile, in correlation with clinicopathological features. PD-L1 and Ki67 were immunohistochemically tested in each case. Furthermore, comprehensive molecular analyses were carried out using NanoString technology and nCounter PanCancer Immune Profiling Panel, and the gene expression results were correlated with clinicopathological characteristics. PD-L1 expression was observed in 13/46 (28.3%) GCTB (and in 1/24, 4.2%, control ABC, only) and associated with a shorter disease free interval according to univariate analysis. Moreover, in PD-L1-positive lesions, three genes (CD27, CD6 and IL10) were significantly upregulated (p < 0.01), while two were downregulated (LCK and TLR8, showing borderline significance, p = 0.06). Interestingly, these genes can be related to maturation and immune tolerance of bone tissue microenvironment, suggesting a more immature/anergic phenotype of giant cell tumors. Our findings suggest that PD-L1 immunoreactivity may help to select GCTB patients with a higher risk of recurrence who could potentially benefit from immune checkpoint blockade.


Assuntos
Antígeno B7-H1/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Tumores de Células Gigantes/genética , Tumores de Células Gigantes/imunologia , Transcriptoma/imunologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Regulação para Baixo/genética , Feminino , Tumores de Células Gigantes/patologia , Humanos , Tolerância Imunológica/genética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Regulação para Cima/genética , Adulto Jovem
4.
DNA Cell Biol ; 39(7): 1181-1193, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32397747

RESUMO

We aimed to establish a novel immunoscore (IS) model based on the transcriptomes of tumor tissues to improve the relapse-free survival (RFS) prediction of colorectal cancer (CRC). CIBERSORT was used to estimate the immune cell fractions based on the Gene Expression Omnibus (GEO) database. Then, a least absolute shrinkage and selection operator regression was applied to construct the IS model based on the immune cell fractions. After screening, four GEO databases were included in the CIBERSORT transformation. A total of 13 types of immune cells were selected and constructed an IS model. In the training set (n = 613) and test set (n = 262), the patients in the high-immunoscore group showed a significant poor RFS than that in the low-immunoscore group. Stratified analysis also found similar results in patients with identical age, sex, adjunctive chemotherapy, or TNM stage I-II. Multivariate Cox regression further demonstrated that the IS model was an independent predictor of RFS in CRC. In addition, the IS was highly associated with the expression of several immune checkpoints, inflammatory mediators, cell cycle, and epithelial-mesenchymal transformation regulators in CRC. We proposed a novel IS model for estimating RFS in CRC patients.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Idoso , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia
5.
DNA Cell Biol ; 39(7): 1194-1204, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32460527

RESUMO

Prostate cancer is the second most common cancer and the fifth cause of cancer death in males. Currently, there are no effective therapies for prostate cancer yet, and the status of treatment remains severe. In this study, we analyzed the composition of tumor-infiltrating immune cells (TIICs) in prostate cancer and paracancerous samples based on the gene expression profiles using CIBERSORT. Calculation of the TIIC subset proportions in 52 paired prostate cancer and paracancerous samples showed that their proportions were similar in intergroup and varied in intragroup. Compared with the paracancerous samples, the proportion of M0 macrophages was significantly increased in prostate cancer samples. Cox regression analysis using the TIIC subpopulations as continuous variables revealed that high plasma cell proportion was associated with poor 3-year Disease-Free Survival (DFS) in prostate cancer (hazard ratios = 1.8e-76, p = 0.001). Moreover, three immune clusters, which presented distinct prognosis, were identified using hierarchical clustering analysis based on the proportions of TIIC subpopulations. Among them, cluster 1 had superior 3-year DFS, while cluster 3 showed inferior 3-year DFS (p = 0.025). In summary, our research provided a comprehensive analysis on the TIIC composition in prostate cancer and suggested that both plasma cells and different cluster patterns were associated with the prostate cancer prognosis, which should be helpful for the clinical surveillance and treatment of prostate cancer.


Assuntos
Biologia Computacional , Sistema Imunitário/citologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Transcriptoma/imunologia , Algoritmos , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Análise de Sobrevida
6.
PLoS Comput Biol ; 16(4): e1007873, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32348312

RESUMO

High-throughput sequencing of B- and T-cell receptors makes it possible to track immune repertoires across time, in different tissues, and in acute and chronic diseases or in healthy individuals. However, quantitative comparison between repertoires is confounded by variability in the read count of each receptor clonotype due to sampling, library preparation, and expression noise. Here, we present a general Bayesian approach to disentangle repertoire variations from these stochastic effects. Using replicate experiments, we first show how to learn the natural variability of read counts by inferring the distributions of clone sizes as well as an explicit noise model relating true frequencies of clones to their read count. We then use that null model as a baseline to infer a model of clonal expansion from two repertoire time points taken before and after an immune challenge. Applying our approach to yellow fever vaccination as a model of acute infection in humans, we identify candidate clones participating in the response.


Assuntos
RNA-Seq/métodos , Receptores de Antígenos de Linfócitos B , Receptores de Antígenos de Linfócitos T , Teorema de Bayes , Biologia Computacional , Humanos , Modelos Imunológicos , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transcriptoma/imunologia , Vacina contra Febre Amarela/imunologia
7.
Nat Immunol ; 21(4): 464-476, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32205882

RESUMO

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.


Assuntos
Transcriptoma/imunologia , Tuberculose/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/microbiologia , Humanos , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/microbiologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Linfócitos T/microbiologia , Tuberculose/microbiologia
8.
PLoS One ; 15(2): e0224775, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084139

RESUMO

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.


Assuntos
Transferência Adotiva/métodos , Neoplasias Ósseas/sangue , Neoplasias Ósseas/veterinária , Doenças do Cão/sangue , Células Matadoras Naturais/imunologia , Osteossarcoma/sangue , Osteossarcoma/veterinária , Cuidados Paliativos/métodos , Animais , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/radioterapia , Citocinas/sangue , Citotoxicidade Imunológica , Doenças do Cão/radioterapia , Cães , Feminino , Seguimentos , Granzimas/metabolismo , Masculino , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Osteossarcoma/radioterapia , Intervalo Livre de Progressão , Transcriptoma/imunologia
9.
Nat Med ; 26(4): 618-629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094927

RESUMO

Responses to vaccination and to diseases vary widely across individuals, which may be partly due to baseline immune variations. Identifying such baseline predictors of immune responses and their biological basis is of broad interest, given their potential importance for cancer immunotherapy, disease outcomes, vaccination and infection responses. Here we uncover baseline blood transcriptional signatures predictive of antibody responses to both influenza and yellow fever vaccinations in healthy subjects. These same signatures evaluated at clinical quiescence are correlated with disease activity in patients with systemic lupus erythematosus with plasmablast-associated flares. CITE-seq profiling of 82 surface proteins and transcriptomes of 53,201 single cells from healthy high and low influenza vaccination responders revealed that our signatures reflect the extent of activation in a plasmacytoid dendritic cell-type I IFN-T/B lymphocyte network. Our findings raise the prospect that modulating such immune baseline states may improve vaccine responsiveness and mitigate undesirable autoimmune disease activity.


Assuntos
Imunidade Adaptativa/genética , Formação de Anticorpos/genética , Vacinas contra Influenza/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transcriptoma , Vacina contra Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Vacinação , Febre Amarela/prevenção & controle , Adulto Jovem
10.
Oncol Rep ; 43(3): 795-806, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020214

RESUMO

Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non­small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10­gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low­risk group was higher than that in the high­risk group, and the difference was statistically significant (P=0.003, P=0.014 and P=0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low­risk group was significantly lower than that in the high­risk group (P=0.05 and P=0.009, respectively). Kaplan­Meier survival results showed that patients of the high­risk group had significantly shorter overall survival (OS) than those of the low­risk group in the training set (P<0.001). Furthermore, Kaplan­Meier survival showed that patients of the high­risk group had significantly shorter OS than those of the low­risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10­gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10­gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Prognóstico , Microambiente Tumoral/imunologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Bases de Dados Genéticas , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , RNA Longo não Codificante/genética , Fatores de Risco , Transcriptoma/imunologia
11.
Infect Immun ; 88(5)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32094254

RESUMO

Localized skin lesions are characteristic of cutaneous leishmaniasis (CL); however, Leishmania (Viannia) species, which are responsible for most CL cases in the Americas, can spread systemically, sometimes resulting in mucosal disease. Detection of Leishmania has been documented in healthy mucosal tissues (conjunctiva, tonsils, and nasal mucosa) and healthy skin of CL patients and in individuals with asymptomatic infection in areas of endemicity of L (V) panamensis and L (V) braziliensis transmission. However, the conditions and mechanisms that favor parasite persistence in healthy mucosal tissues are unknown. In this descriptive study, we compared the cell populations of the nasal mucosa (NM) of healthy donors and patients with active CL and explored the immune gene expression signatures related to molecular detection of Leishmania in this tissue in the absence of clinical signs or symptoms of mucosal disease. The cellular composition and gene expression profiles of NM samples from active CL patients were similar to those of healthy volunteers, with a predominance of epithelial over immune cells, and within the CD45+ cell population, a higher frequency of CD66b+ followed by CD14+ and CD3+ cells. In CL patients with molecular evidence of Leishmania persistence in the NM, genes characteristic of an anti-inflammatory and tissue repair responses (IL4R, IL5RA, POSTN, and SATB1) were overexpressed relative to NM samples from CL patients in which Leishmania was not detected. Here, we report the first immunological description of subclinically infected NM tissues of CL patients and provide evidence of a local anti-inflammatory environment favoring parasite persistence in the NM.


Assuntos
Leishmaniose Cutânea/imunologia , Mucosa Nasal/imunologia , Adulto , Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/imunologia , Subunidade alfa de Receptor de Interleucina-5/imunologia , Leishmania/imunologia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/imunologia , Pele/imunologia , Transcriptoma/imunologia
12.
Cancer Res ; 80(5): 1078-1087, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31948941

RESUMO

Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR- macrophages. The HLA-DR- subset coexpressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy. SIGNIFICANCE: These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.


Assuntos
Biomarcadores Tumorais/análise , Macrófagos/imunologia , Melanoma/mortalidade , Pele/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Feminino , Imunofluorescência , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Melanoma/sangue , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco/métodos , Pele/imunologia , Linfócitos T Citotóxicos/imunologia , Transcriptoma/imunologia , Microambiente Tumoral/genética , Adulto Jovem
13.
PLoS One ; 15(1): e0223397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923202

RESUMO

Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the local cells that often come in form of secreted factors, such as cytokines. These factors are known to impact the immune cells' biology. However, very little is known about whether the tissue resident immune cells in return also affect the local environment. In this study, with the help of RNA-sequencing, we show for the first time that long-term absence of epidermal resident Langerhans cells led to significant gene expression changes in the local keratinocytes and resident dendritic epidermal T cells. Thus, immune cells might play an active role in maintaining tissue homeostasis, which should be taken in consideration at data interpretation.


Assuntos
Citocinas/genética , Queratinócitos/metabolismo , Células de Langerhans/metabolismo , Transcriptoma/genética , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epidérmicas/imunologia , Células Epidérmicas/metabolismo , Regulação da Expressão Gênica/genética , Homeostase/imunologia , Humanos , Queratinócitos/imunologia , Células de Langerhans/imunologia , Análise de Componente Principal , Alinhamento de Sequência , Análise de Sequência de RNA , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/imunologia
14.
Int J Med Sci ; 17(1): 89-96, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929742

RESUMO

Bladder cancer is one of the most commonly diagnosed tumors and is results from the accumulation of somatic mutations in the DNA. Tumor mutation burden (TMB) has been associated with cancer immunotherapeutic response. In this study, we attempted to explore the correlation between TMB and cancer prognosis. Identify the different expressed genes and immune cell infiltration signatures between low and high TMB group. Mutation data, gene expression profiles and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups, allowing differentially expressed genes (DEGs) to be identified. Functional enrichment and protein-protein interaction (PPI) network analysis were used to identify the functions of the DEGs. And immune cell infiltration signatures were evaluated by CIBERSORT algorithm. These results shown that high TMB was significantly associated with prognosis. We obtained a list of TMB related genes which may influence the infiltrations of immune cells. We also found a higher proportion of CD8 T cells, CD4 T cells and NK cells in the high TMB group. Our data suggest that higher TMB tends to promote the infiltrations of T cells and NK cells and patients with higher TMB may achieve a more favorable prognosis in bladder cancer.


Assuntos
Biomarcadores Tumorais/genética , Quimiocina CXCL10/genética , Proteínas de Neoplasias/genética , Neoplasias da Bexiga Urinária/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Transdução de Sinais/genética , Transcriptoma/genética , Transcriptoma/imunologia , Carga Tumoral/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
15.
Nat Immunol ; 21(2): 221-231, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959980

RESUMO

The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly understood. In the present study, systematic evaluation of transcriptomes and open chromatin of alveolar macrophages (AMs), interstitial macrophages (IMs) and lung monocytes from two mouse strains enabled inference of common and cell-specific transcriptional regulators. We provide evidence that these factors drive selection of regulatory landscapes that specify distinct phenotypes of AMs and IMs and entrain qualitatively different responses to toll-like receptor 4 signaling in vivo. These studies reveal a striking divergence in a fundamental innate immune response pathway in AMs and establish a framework for further understanding macrophage diversity in the lung.


Assuntos
Imunidade Inata/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Animais , Epigênese Genética/imunologia , Macrófagos/citologia , Camundongos , Monócitos/citologia , Transcriptoma/imunologia
16.
Mol Immunol ; 117: 147-154, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790863

RESUMO

Based on the large number of deaths of lamprey larvae infected by pathogens in the culture process, the infection response of lamprey larvae to different pathogens was studied. Thus, high-throughput sequencing is firstly used to analyze the lamprey larvae infected by Aeromonas hydrophila, Vibrosplendidus, and Saprolegnia parasitica. A high quality of 338,628,426 Reads were obtained and 203,829 transcripts were assembled. A total of 158,001 Unigenes were annotated by Blast comparison, and a relatively comprehensive transcriptome database of lamprey larvae was established. Based on the transcriptome of lamprey larvae infected by three aquatic pathogens, classification results of COG and GO show that the genes classified into signal transduction mechanism accounted for the largest proportion, and 2316 differentially expressed genes were identified and screened out. After infection by the three pathogens, 16 genes and 19 genes expression were up-regulated and down-regulated, respectively. KEGG pathway analysis of differentially expressed genes showed that lamprey larvae were mainly affected their metabolism and oxidative phosphorylation pathways after infection by two gram-negative bacteria, Vibrosplendidus and Aeromonas hydrophila. As a fungus, Saprolegnia parasitica mainly affected ribosome synthesis in lamprey larvae. The results were validated by detecting the expression levels of 13 DEGs at 24 h after pathogens treatment using Q-PCR. The results provide valuable information for further research into the development of immunity and the innate immune response against pathogen invasion during the artificial propagation of lamprey larvae.


Assuntos
Doenças dos Peixes/imunologia , Lampreias/imunologia , Transcriptoma/imunologia , Aeromonas hydrophila/imunologia , Animais , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica , Imunidade Inata/imunologia , Infecções/imunologia , Larva , Saprolegnia/imunologia , Vibrio/imunologia
17.
Ann Rheum Dis ; 79(2): 242-253, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31780527

RESUMO

OBJECTIVES: Haematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs. METHODS: A global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence. RESULTS: Transcriptomic analysis of Lin-Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)-but not of common lymphoid progenitors-reminiscent of a 'trained immunity' signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data. CONCLUSIONS: Aberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare. TRIAL REGISTRATION NUMBER: 4948/19-07-2016.


Assuntos
Reprogramação Celular/imunologia , Células-Tronco Hematopoéticas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Células Mieloides/imunologia , Transcriptoma/imunologia , Animais , Apoptose/imunologia , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Ciclo Celular/imunologia , Mapeamento Cromossômico , Dano ao DNA , Citometria de Fluxo , Imunofluorescência , Fator Estimulador de Colônias de Granulócitos/metabolismo , Granulócitos/imunologia , Linfócitos/imunologia , Camundongos
18.
Fish Shellfish Immunol ; 96: 32-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786343

RESUMO

The red-swamp crayfish (Procambarus clarkii) is the most important economic shrimp species in China, and is an important model crustacean organism in many fields of research. In crustaceans, gills interface directly with the ambient environment and thus play a vital role in the toxicology. In the context of increasing environmental heavy metal pollution, the relationship between copper (Cu2+) stress and the immune response of P. clarkii has recently received considerable attention. However, impact of Cu2+ on the crayfish immune system is still not fully understood. In this study, we used Illumina sequencing technology to perform a transcriptome analysis of the gills of P. clarkii after 24 h of Cu2+ treatment. A total of 37,226,812 unigenes were assembled, and 1943 unigenes were significantly differentially expressed between the control and Cu2+ treatment groups. Functional categorization of differentially expressed genes (DEGs) revealed that genes related to antioxidant activity, detoxication, metabolic processes, biosynthetic processes, and immune system processes were differentially regulated during Cu2+ stress. In addition, DEGs in the immune system were classified as being related to the MAPK signaling pathway, purine metabolism, Toll and Imd signaling pathway, PI3K-Akt signaling pathway and Hippo signaling pathway. Five genes (CuZnSOD, CAT, IDH1, PHYH and DECR2) were significantly up-regulated in the peroxisome pathway, which plays an important role in reacting to oxidative stress. Importantly, qRT-PCR validation of the results for seven genes chosen at random (NDK, ATP6L, ATP5C1, RPS14, RPL22e, CTSF and HSP90A) confirmed the Illumina sequencing results. This study provides a valuable starting point for further studies to elucidate the molecular basis of the immune system's response to Cu2+ stress in crayfish.


Assuntos
Astacoidea/genética , Astacoidea/imunologia , Cobre/efeitos adversos , Imunidade Inata/genética , Transcriptoma/imunologia , Poluentes Químicos da Água/efeitos adversos , Animais , Astacoidea/efeitos dos fármacos , Perfilação da Expressão Gênica , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Distribuição Aleatória , Estresse Fisiológico , Transcriptoma/efeitos dos fármacos
19.
J Exp Med ; 217(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31570496

RESUMO

CCR6- group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6- ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6- ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Animais , Linhagem da Célula/imunologia , Cromatina/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fatores de Transcrição/imunologia , Transcriptoma/imunologia
20.
Nat Med ; 25(12): 1916-1927, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792460

RESUMO

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.


Assuntos
Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Mutação/genética , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma/genética , Transcriptoma/imunologia , Sequenciamento Completo do Exoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA