Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 802
Filtrar
1.
Nat Commun ; 12(1): 1426, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658518

RESUMO

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Antígenos B7/genética , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulação Neoplásica da Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Masculino , Inclusão em Parafina , Fenótipo , Receptor de Morte Celular Programada 1/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Análise Serial de Tecidos , Transcriptoma
2.
Nat Med ; 27(2): 256-263, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33558721

RESUMO

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Interferon gama/genética , Ipilimumab/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Mutação/genética , Terapia Neoadjuvante/efeitos adversos , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Recidiva
3.
Nat Commun ; 12(1): 959, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574239

RESUMO

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).


Assuntos
Doença de Addison/genética , Estudo de Associação Genômica Ampla , Fatores de Transcrição de Zíper de Leucina Básica/genética , Antígeno CTLA-4/genética , Feminino , Humanos , Masculino , Modelos Moleculares , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Risco
4.
Nat Commun ; 12(1): 808, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547292

RESUMO

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , /imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia
5.
Nat Commun ; 12(1): 525, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483505

RESUMO

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.


Assuntos
Subpopulações de Linfócitos B/imunologia , Antígeno CTLA-4/imunologia , Homeostase/imunologia , Sistema Imunitário/imunologia , Tolerância Imunológica/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Diferenciação Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
6.
Nucleic Acids Res ; 49(3): 1235-1246, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33398344

RESUMO

We have identified chemical probes that simultaneously inhibit cancer cell progression and an immune checkpoint. Using the computational Site Identification by Ligand Competitive Saturation (SILCS) technology, structural biology and cell-based assays, we identify small molecules that directly and selectively bind to the RNA Recognition Motif (RRM) of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 recognizes a specific RNA signature motif in the 3'UTR of transcripts associated with cancer cell progression (Trx, VEGF, RPA) and, as shown here, a tumor immune checkpoint (CTLA-4). Post-transcriptional regulation of immune checkpoints is a potential therapeutic strategy that remains to be exploited. The probes target hnRNP A18 RRM in vitro and in cells as evaluated by cellular target engagement. As single agents, the probes specifically disrupt hnRNP A18-RNA interactions, downregulate Trx and CTLA-4 protein levels and inhibit proliferation of several cancer cell lines without affecting the viability of normal epithelial cells. These first-in-class chemical probes will greatly facilitate the elucidation of the underexplored biological function of RNA Binding Proteins (RBPs) in cancer cells, including their effects on proliferation and immune checkpoint activation.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Humanos , Ligantes , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Ressonância Magnética Nuclear Biomolecular , Biossíntese de Proteínas , RNA/metabolismo , Motivo de Reconhecimento de RNA , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo
7.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
8.
Medicine (Baltimore) ; 99(50): e23519, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327297

RESUMO

BACKGROUND: Previous published studies have reported the association of cytotoxic T lymphocyte antigen 4 (CTLA-4) genetic polymorphisms with the susceptibility to head and neck cancer, but the results remain controversial. We therefore will conduct a meta-analysis to investigate the relationship between CTLA-4 genetic polymorphisms and head and neck cancer susceptibility. METHODS: We will systematically search case-control studies for potential eligible studies from Cochrane Library, EMBASE, Google Scholar, PubMed, China Biomedical Database, WanFang database, and China National Knowledge Infrastructure (CNKI). Additionally, we will also examine other sources to avoid missing potential trials. Two authors will independently collect and perform the study selection, data extraction, and study methodological quality. Statistical analyses were utilized using STATA 12.0 and RevMan 5.3, and the odds ratios (ORs) with 95% confidence intervals (95% CI) were used to estimate the strength of the association of CTLA-4 genetic polymorphisms with the susceptibility to head and neck cancer. RESULTS: This protocol study will assess the relationship between CTLA-4 genetic polymorphisms and head and neck cancer susceptibility. CONCLUSION: The findings of this study will provide systematic evidence for future guidance developing and clinical decision making in patients with head and neck cancer. ETHICS AND DISSEMINATION: Ethical approval will not be required as this study is a systematic review. PROTOCOL REGISTRATION NUMBER: DOI 10.17605/OSF.IO/BFJTZ (https://osf.io/bfjtz/).


Assuntos
Antígeno CTLA-4/genética , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Grupo com Ancestrais do Continente Asiático , China , Humanos , Polimorfismo Genético
9.
Medicine (Baltimore) ; 99(50): e23542, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327303

RESUMO

BACKGROUND: We performed a meta-analysis to more precisely evaluate the association between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) -1772T/C polymorphism and overall gastric cancer (GC) risk and the influence of ethnicity and the source of controls on that association. METHODS: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, Web of Science (WOS) Database, Chinese National Knowledge Infrastructure (CNKI), China biomedical literature database (CBM), Wanfang database, and VIP. Two investigators independently reviewed the articles, and disagreements were resolved by discussion and consensus. The odds ratio (OR) with 95% confidence intervals (CIs) was used to assess the strength of the association between the CTLA-4 -1722T/C polymorphism and GC risk, based on the genotype frequencies in cases and controls. The meta-analyses were performed with Stata 12.0, using two-sided P values. Trial sequential analysis (TSA) was calculated by TSA Software. RESULTS: Overall, we identified 5 studies including 1039 GC cases and 2136 controls that evaluated the association of the CTLA-4 -1722T/C polymorphism and GC risk. Overall, there was no significant association between the CTLA-4-1722T/C polymorphism and the risk of GC. In the subgroup analysis based on ethnicity, the results showed that the relationship between the CTLA-4 -1722T/C polymorphism and GC susceptibility was strongest in the Chinese population rather than in the Iranian population (TC vs CC: OR = 1.405, 95% CI: 1.100-1.796, P = .007; TC+TT vs CC: OR = 1.329, 95% CI: 1.052-1.680, P = .017). Then, there was a significant association between the CTLA-4 -1722T/C polymorphism and the risk of GC in studies with HB controls. However, the above correlation can only be reflected in specific populations and gene models. Therefore, we believe that the evidence of this correlation is insufficient. CONCLUSION: Our meta-analysis showed that the CTLA-4 -1722T/C polymorphism may be associated with the susceptibility to GC. However, the slight correlation can only be reflected in specific populations and gene models. Therefore, we believe that this association is negligible. The large and well-designed case-control studies are needed to validate our findings.


Assuntos
Antígeno CTLA-4/genética , Neoplasias Gástricas/genética , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética
10.
Lancet Oncol ; 21(11): 1465-1477, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961119

RESUMO

BACKGROUND: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results. METHODS: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906. FINDINGS: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported. INTERPRETATION: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Intervalo Livre de Doença , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/genética , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Resultado do Tratamento
11.
PLoS One ; 15(9): e0239426, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946523

RESUMO

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample.


Assuntos
Artrite Reumatoide/genética , Antígeno CTLA-4/genética , Análise de Sequência , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único
12.
Arch Virol ; 165(10): 2249-2258, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32696270

RESUMO

While infectious bursal disease virus (IBDV) mainly targets immature B cells and causes T cell infiltration in the bursa of Fabricius (BF) of chickens, the effect of IBDV infection on the properties of T cells and relevant cytokine production in avian gut-associated lymphoid tissues (GALTs) remains unknown. Here, we show that while the CD8+ T cell subset is not affected, IBDV infection decreases the percentage of CD4+ T cells in the cecal tonsil (CT), but not in esophagus tonsil, pylorus tonsil, and Meckel's diverticulum of GALTs, in contrast to BF and spleen, in which the proportion of CD4+ cells increases upon IBDV infection. Further, IBDV infection upregulates IFN-γ, IL-10, and the T cell checkpoint receptor LAG-3 mRNA expression in BF. In contrast, in CTs, IBDV infection significantly increases the production of IFN-ß and CTLA-4 mRNA, while no significant effect is seen in the case of IFN-γ, IL-10 and LAG-3. Together, our data reveal differential modulation of T cell subsets and proinflammatory cytokine production in different lymphoid tissues during the course of IBDV infection.


Assuntos
Subpopulações de Linfócitos B/imunologia , Infecções por Birnaviridae/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , Doenças das Aves Domésticas/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Subpopulações de Linfócitos B/virologia , Infecções por Birnaviridae/genética , Infecções por Birnaviridae/patologia , Infecções por Birnaviridae/virologia , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Galinhas/virologia , Vírus da Doença Infecciosa da Bursa/crescimento & desenvolvimento , Vírus da Doença Infecciosa da Bursa/imunologia , Vírus da Doença Infecciosa da Bursa/patogenicidade , Interferon beta/genética , Interferon beta/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Tonsila Palatina/imunologia , Tonsila Palatina/virologia , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/virologia
13.
Sheng Wu Gong Cheng Xue Bao ; 36(5): 969-978, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32567280

RESUMO

Drugs targeting immune checkpoint are used for cancer treatment, but resistance to single drug may occur. Combination therapy blocking multiple checkpoints simultaneously can improve clinical outcome. Therefore, we designed a recombinant protein rPC to block multiple targets, which consists of extracellular domains of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The coding sequence was inserted into expression vector and stably transfected into HEK293 cells. The culture supernatant was collected and rPC was affinity-purified. Real-time quantitative PCR was used to evaluate the expression levels of ligands for PD-1 and CTLA-4 in several human cancer cell lines. The binding of rPC with cancer cells was examined by immunofluorescence cell staining, the influence of rPC on cancer cell growth was assayed by CCK-8. The results showed that rPC could be expressed and secreted by stably transfected HEK293 cells, the purified rPC could bind to lung cancer NCI-H226 cells which have high levels of ligands for PD-1 and CTLA-4, no direct impact on cancer cell growth could be observed by rPC treatment. The recombinant protein rPC can be functionally assayed further for developing novel immunotherapeutic drugs for cancer.


Assuntos
Neoplasias Pulmonares , Proteínas Recombinantes de Fusão , Animais , Antígeno CTLA-4/genética , Proliferação de Células , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Domínios Proteicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo
14.
Gene ; 754: 144838, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525043

RESUMO

In recent years, conclusive data have emerged on a relationship between immune system, especially the T-cell, and blood pressure (BP). The objective of the present study was to determine the association between BP and four polymorphisms in CD80, CD86, CD28 and CTLA4 genes that code for key proteins in the T-cell co-stimulation process, in a female cohort. To that end, an association study in a cohort of 934 women over 40 years old from two hospitals was done. Raw data showed a significant association between the SNP rs1129055 of CD86 gene and BP. Analyzing this association against inheritance patterns, higher SBP (p < 0.000) and DBP (p = 0.005) values were observed in AA than in GG/GA genotype subjects in the largest sample cohort (Hospital 1). In multivariate linear regression studies, with adjustment for presumed independent predictors of BP, the SNP of the CD86 gene remained a predictor of SBP (p = 0.001) and DBP (p = 0.006), as did the SNP rs867234 of the CD80 gene for DBP (p < 0.000), both resisting the Bonferroni correction for multiple comparisons. As conclusion, we report a robust association between the SNP rs1129055 of CD86 gene and BP. The SNP rs867234 of CD80 gene was also shown to be a strong predictor of DBP.


Assuntos
Antígeno B7-1/genética , Antígeno B7-2/genética , Pressão Sanguínea , Antígenos CD28/genética , Antígeno CTLA-4/genética , Polimorfismo de Nucleotídeo Único , Linfócitos T/metabolismo , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Linfócitos T/citologia
15.
Cancer Immunol Immunother ; 69(10): 1989-1999, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32393998

RESUMO

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CTLA-4/sangue , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/sangue , Receptores Imunológicos/sangue , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Linfócitos T/patologia , Adulto Jovem
16.
An Bras Dermatol ; 95(3): 283-288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32278632

RESUMO

BACKGROUND: Alopecia areata is an autoimmune disease that produces non-scarring hair loss around the body. Gene variants of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a negative regulator of T-cell response, have been associated with a predisposition to autoimmune diseases in different populations; however, the involvement of these genetic variants in the development of AA is controversial. OBJECTIVE: The present study evaluated the potential association of two CTLA4 gene variants with alopecia areata in a Mexican population. METHODS: We genotyped +49AG (rs231775) and CT60 (rs3087243) variants in 50 AA patients and 100 healthy control participants through PCR-RFLP. RESULTS: No statistical difference was observed for either of the gene variants regarding allele or genotype frequencies between AA patients and the controls when the parameters of family/personal history of autoimmune diseases or gender were considered (p>0.05). STUDY LIMITATIONS: Small sample size of patients and the data were obtained from Northeast Mexico population. CONCLUSION: The genetic variants rs231775 and rs3087243 of the CTLA4 gene are not a risk factor for the development of alopecia areata in the analyzed Mexican population.


Assuntos
Alopecia em Áreas/genética , Antígeno CTLA-4/genética , Variação Genética/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Masculino , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
17.
Medicine (Baltimore) ; 99(11): e19433, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176070

RESUMO

BACKGROUND: Number of studies have been performed to evaluate the relationship between the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) gene variant rs5742909 polymorphism and cervical cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association. METHODS: PubMed, Web of Science, Embase, China Biology Medical Literature database, China National Knowledge Infrastructure, WanFang, and Weipu databases were searched before July 31, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0. RESULTS: Eleven studies involved 3899 cases and 4608 controls. Overall, significant association was observed between the CTLA-4 gene variant rs5742909 polymorphism and cervical cancer (T vs C: OR = 1.40, 95% CI = 1.12-1.76; TT vs CC: OR = 2.22, 95% CI = 1.13-4.37; TT vs CT+CC: OR = 1.96, 95% CI = 1.03-3.74; TT+CT vs CC: OR = 1.47, 95% CI = 1.14-1.90). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.56, 95% CI = 1.22-1.99), but not in Caucasians (T vs C: OR = 1.19, 95% CI = 0.87-1.62). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. CONCLUSION: our meta-analysis supports that the CTLA-4 gene variant rs5742909 polymorphism might contribute to individual susceptibility to cervical cancer in Asians.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Antígeno CTLA-4/genética , Predisposição Genética para Doença/etnologia , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/genética , Feminino , Humanos
18.
Adv Exp Med Biol ; 1248: 227-250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185713

RESUMO

In this chapter, we will sketch a story that begins with the breakdown of chromosome homeostasis and genomic stability. Genomic alterations may render tumor cells eternal life at the expense of immunogenicity. Although antitumor immunity can be primed through neoantigens or inflammatory signals, tumor cells have evolved countermeasures to evade immune surveillance and strike back by modulating immune checkpoint related pathways. At present, monoclonal antibody drugs targeting checkpoints like PD-1 and CTLA-4 have significantly prolonged the survival of a variety of cancer patients, and thus have marked a great achievement in the history of antitumor therapy. Nevertheless, this is not the end of the story. As the relationship between genomic alteration and checkpoint expression is being delineated though the advances of preclinical animal models and emerging technologies, novel checkpoint targets are on the way to be discovered.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Descoberta de Drogas , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
19.
Gene ; 737: 144435, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044407

RESUMO

The cancer-brake gene CTLA4 has a vital function in suppressing the immune responses of activated T lymphocytes. Numerous reports explored the impact of various CTLA4 variants with the predisposition for malignancies but with unconvincing findings. Hence, this study is designed to assess the association of CTLA4 (c.49A>G, rs231775) variant with the outcome of breast carcinoma. A total of 272 participants (93 BC patients and 179 cancer-free healthy volunteers) were enrolled. Genomic DNA for all participants was genotyped for CTLA4 (c.49A>G) variant via TaqMan genotyping assay. Patients with A/G genotype conferred protection against developing BC under heterozygote comparison (OR = 0.56, 95%CI = 0.31-0.98) as well dominant model (OR = 0.55, 95%CI = 0.32-0.97). AG/GG genotypes were anchored with an increased risk of nodal infiltration (OR = 2.90, 95%CI = 1.03-8.17, P = 0.037), metastasis (OR = 4.46, 95%CI = 1.18-16.8, P = 0.019), advanced clinical stage (OR = 6.54, 95%CI = 2.06-20.75, P < 0.001), recurrence (OR = 5.2, 95%CI = 1.73-15.7, P = 0.001), and shorter survival (OR = 2.54, 95%CI = 1.08-5.99, P = 0.032). In addition, functional enrichment analysis revealed the key role of CTLA4 in cancer immunosurveillance. Our findings indicated that the CTLA4 c.49A>G variant might have prognostic as well diagnostic impact in breast cancer.


Assuntos
Neoplasias da Mama/genética , Antígeno CTLA-4/genética , Mutação de Sentido Incorreto , Sinais Direcionadores de Proteínas , Adulto , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Egito , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...