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[PMID]:28922790
[Au] Autor:Marisa L; Svrcek M; Collura A; Becht E; Cervera P; Wanherdrick K; Buhard O; Goloudina A; Jonchère V; Selves J; Milano G; Guenot D; Cohen R; Colas C; Laurent-Puig P; Olschwang S; Lefèvre JH; Parc Y; Boige V; Lepage C; André T; Fléjou JF; Dérangère V; Ghiringhelli F; de Reynies A; Duval A
[Ad] Endereço:Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe "Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC U
[Ti] Título:The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Biomarcadores Tumorais/imunologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/imunologia
Linfócitos do Interstício Tumoral
Linfócitos T Citotóxicos
[Mh] Termos MeSH secundário: Antígenos CD/genética
Antígeno B7-H1/análise
Antígeno B7-H1/genética
Antígenos CD8/análise
Antígeno CTLA-4/genética
Colo/química
Neoplasias Colorretais/química
Neoplasias Colorretais/patologia
Feminino
Expressão Gênica
Receptor Celular 2 do Vírus da Hepatite A/genética
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Masculino
Instabilidade de Microssatélites
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Proteína 2 Ligante de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/genética
Estudos Retrospectivos
Taxa de Sobrevida
Células Th1
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antigens, CD); 0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD223 antigen); 0 (CD274 protein, human); 0 (CD8 Antigens); 0 (CTLA-4 Antigen); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (PDCD1LG2 protein, human); 0 (Programmed Cell Death 1 Ligand 2 Protein); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx136


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[PMID]:28880903
[Au] Autor:Goods BA; Hernandez AL; Lowther DE; Lucca LE; Lerner BA; Gunel M; Raddassi K; Coric V; Hafler DA; Love JC
[Ad] Endereço:Departments of Biological Engineering and Chemical Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
[Ti] Título:Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme.
[So] Source:PLoS One;12(9):e0181538, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/metabolismo
Glioblastoma/metabolismo
Receptor de Morte Celular Programada 1/metabolismo
[Mh] Termos MeSH secundário: Anticorpos Bloqueadores/uso terapêutico
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD8-Positivos/efeitos dos fármacos
Linfócitos T CD8-Positivos/metabolismo
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Citometria de Fluxo
Glioblastoma/imunologia
Voluntários Saudáveis
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Seres Humanos
Interferon gama/metabolismo
Interleucina-2/uso terapêutico
Telômero/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Blocking); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (Interleukin-2); 0 (Programmed Cell Death 1 Receptor); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181538


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[PMID]:28771603
[Au] Autor:Arbour KC; Naidoo J; Steele KE; Ni A; Moreira AL; Rekhtman N; Robbins PB; Karakunnel J; Rimner A; Huang J; Riely GJ; Hellmann MD
[Ad] Endereço:Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
[Ti] Título:Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors.
[So] Source:PLoS One;12(8):e0182665, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. METHODS: Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. RESULTS: PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p<0.01), and was associated with longer overall survival (p = 0.02). TIM-3 and GITR were expressed in all TETs, including 18/23 and 12/23 with at least moderate/high expression, respectively. Moderate/high CD137 expression correlated with CD8+ (p = 0.01) and moderate/high GITR expression co-associated with PD-1 (p = 0.043). CONCLUSIONS: TETs are characterized by frequent PD-L1 expression and PD-L1 is associated with improved survival, suggesting PD-L1 signaling may be biologically important in TETs. Robust expression of markers of immune activation and immunotherapeutic target molecules in TETs emphasizes the potential for development of anti-PD-1/PD-L1 therapies.
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Biomarcadores Tumorais/metabolismo
Neoplasias Epiteliais e Glandulares/imunologia
Timoma/imunologia
Neoplasias do Timo/imunologia
[Mh] Termos MeSH secundário: Antígeno B7-H1/imunologia
Linfócitos T CD8-Positivos/imunologia
Antígeno CTLA-4/metabolismo
Feminino
Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Seres Humanos
Subpopulações de Linfócitos/imunologia
Linfócitos do Interstício Tumoral/imunologia
Masculino
Análise de Sobrevida
Análise Serial de Tecidos
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (CTLA-4 Antigen); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (TNFRSF18 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182665


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[PMID]:28756232
[Au] Autor:Luo LH; Li DM; Wang YL; Wang K; Gao LX; Li S; Yang JG; Li CL; Feng W; Guo H
[Ad] Endereço:Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
[Ti] Título:Tim3/galectin-9 alleviates the inflammation of TAO patients via suppressing Akt/NF-kB signaling pathway.
[So] Source:Biochem Biophys Res Commun;491(4):966-972, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Studies showed that T helper 1 (Th1), Th2, and Th17 cells play important roles in the pathology of TAO. Tim-3 and its only known ligand Galectin-9 (Gal-9) is related to the suppression of Th1 and Th17 cytokine secretion. This study aims to investigate the role of Tim3/Gal-9 in the inflammatory response of TAO. In this study, the levels of Tim3, Gal-9, and cytokines of Th1 (TNF-α and IFN-γ), Th2 (IL-4), and Th17 (IL-17) cells were analyzed in the blood samples of TAO patients and healthy controls as well as in orbital fibroblasts. Tim3 overexpression and Gal-9 neutralizing antibody were used in TAO and LPS-stimulated control orbital fibroblasts to further investigate the role and mechanism of Tim3/Gal-9 on the inflammation of TAO. We found Tim3 and Gal-9 expression was significantly downregulated in TAO patients and further lower in active TAO than inactive TAO or controls. Th1, Th2, and Th17 cytokines were all increased in TAO patients. Th1 and Th17 cytokines were higher in active TAO patients than in inactive TAO patients, while Th2 cytokines were enhanced in inactive TAO. Tim3 overexpression decreased the levels of Th1 and Th17 cytokines, but not Th2 cytokine in TAO or LPS-stimulated control orbital fibroblasts. These effects were abrogated by Gal-9 neutralizing antibody. Moreover, Tim3 reduced the levels of p-Akt and p-p65 in TAO or LPS-induced control orbital fibroblasts that were reversed by Gal-9 blocking. In conclusion, Tim3/Gal-9 alleviates the inflammation of TAO patients via suppressing Akt/NF-κB signaling pathway.
[Mh] Termos MeSH primário: Galectinas/metabolismo
Oftalmopatia de Graves/metabolismo
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Inflamação/metabolismo
NF-kappa B/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adulto
Feminino
Seres Humanos
Masculino
Meia-Idade
NF-kappa B/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Galectins); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (LGALS9 protein, human); 0 (NF-kappa B); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170731
[St] Status:MEDLINE


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[PMID]:28723950
[Au] Autor:Ryser S; Estellés A; Tenorio E; Kauvar LM; Gishizky ML
[Ad] Endereço:Trellis Bioscience LLC, Menlo Park, California, United States of America.
[Ti] Título:High affinity anti-TIM-3 and anti-KIR monoclonal antibodies cloned from healthy human individuals.
[So] Source:PLoS One;12(7):e0181464, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report here the cloning of native high affinity anti-TIM-3 and anti-KIR IgG monoclonal antibodies (mAbs) from peripheral blood mononuclear cells (PBMC) of healthy human donors. The cells that express these mAbs are rare, present at a frequency of less than one per 105 memory B-cells. Using our proprietary multiplexed screening and cloning technology CellSpot™ we assessed the presence of memory B-cells reactive to foreign and endogenous disease-associated antigens within the same individual. When comparing the frequencies of antigen-specific memory B-cells analyzed in over 20 screening campaigns, we found a strong correlation of the presence of anti-TIM-3 memory B-cells with memory B-cells expressing mAbs against three disease-associated antigens: (i) bacterial DNABII proteins that are a marker for Gram negative and Gram positive bacterial infections, (ii) hemagglutinin (HA) of influenza virus and (iii) the extracellular domain of anaplastic lymphoma kinase (ALK). One of the native anti-KIR mAbs has similar characteristics as lirilumab, an anti-KIR mAb derived from immunization of humanized transgenic mice that is in ongoing clinical trials. It is interesting to speculate that these native anti-TIM-3 and anti-KIR antibodies may function as natural regulatory antibodies, analogous to the pharmacological use in cancer treatment of engineered antibodies against the same targets. Further characterization studies are needed to define the mechanisms through which these native antibodies may function in healthy and disease conditions.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/imunologia
Receptor Celular 2 do Vírus da Hepatite A/imunologia
Leucócitos Mononucleares/imunologia
Receptores KIR/imunologia
[Mh] Termos MeSH secundário: Especificidade de Anticorpos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (Receptors, KIR)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181464


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[PMID]:28687658
[Au] Autor:Gibson A; Faulkner L; Lichtenfels M; Ogese M; Al-Attar Z; Alfirevic A; Esser PR; Martin SF; Pirmohamed M; Park BK; Naisbitt DJ
[Ad] Endereço:Department of Molecular and Clinical Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, United Kingdom.
[Ti] Título:The Effect of Inhibitory Signals on the Priming of Drug Hapten-Specific T Cells That Express Distinct Vß Receptors.
[So] Source:J Immunol;199(4):1223-1237, 2017 Aug 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Drug hypersensitivity involves the activation of T cells in an HLA allele-restricted manner. Because the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell-priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vß subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses. An expansion of the TCR repertoire was observed for nine Vß subtypes, whereas spectratyping revealed that SMX-NO-specific T cell responses are controlled by public TCRs present in all individuals alongside private TCR repertoires specific to each individual. We proceeded to evaluate the extent to which the activation of these TCR Vß-restricted Ag-specific T cell responses is governed by regulatory signals. Blockade of PD-L1/CTLA4 signaling dampened activation of SMX-NO-specific naive and memory T cells, whereas blockade of TIM-3 produced no effect. Programmed death-1, CTLA4, and TIM-3 displayed discrete expression profiles during drug-induced T cell activation, and expression of each receptor was enhanced on dividing T cells. Because these receptors are also expressed on Tregs, Treg-mediated suppression of SMX-NO-induced T cell activation was investigated. Tregs significantly dampened the priming of T cells. In conclusion, our findings demonstrate that distinct TCR Vß subtypes, dysregulation of coinhibitory signaling pathways, and dysfunctional Tregs may influence predisposition to hypersensitivity.
[Mh] Termos MeSH primário: Haptenos/imunologia
Ativação Linfocitária
Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
Subpopulações de Linfócitos T/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Linfócitos T CD4-Positivos/imunologia
Antígeno CTLA-4/metabolismo
Hipersensibilidade a Drogas
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Seres Humanos
Memória Imunológica
Receptor de Morte Celular Programada 1/metabolismo
Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores
Receptores de Antígenos de Linfócitos T alfa-beta/genética
Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
Sulfametoxazol/análogos & derivados
Sulfametoxazol/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (HAVCR2 protein, human); 0 (Haptens); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 0 (Receptors, Antigen, T-Cell, alpha-beta); 131549-85-4 (4-nitrososulfamethoxazole); JE42381TNV (Sulfamethoxazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1602029


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[PMID]:28681697
[Au] Autor:Piao Y; Jin X
[Ad] Endereço:1 Department of Urology, Affiliated Hospital of Yanbian University, Yanji, China.
[Ti] Título:Analysis of Tim-3 as a therapeutic target in prostate cancer.
[So] Source:Tumour Biol;39(7):1010428317716628, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tim-3 (T-cell immunoglobulin domain and mucin domain-containing molecule 3) is a newly discovered immunomodulatory protein, which plays an important role in immunity regulation. Recent evidence suggests that Tim-3 is differentially regulated in a variety of tumors and has potential as a therapeutic target. The aim of this study was to investigate the effect of Tim-3 on the development of prostate cancer. Tim-3 expressing on peripheral CD4+ T and CD8+ T cells was analyzed by flow cytometry. The relationships between Tim-3 expression and clinicopathological features were analyzed. Immunohistochemical expression of Tim-3 was examined in our large numbers of paraffin-fixed prostate tissues. Flow cytometry revealed that expression of Tim-3 was significantly increased on both CD4+ and CD8+ T cells in prostate cancer patients than that in benign prostate hyperplasia patients. Also, the level of Tim-3 on CD4+ T cells was positively correlated with CD8+ T cells in patients. Further analyses revealed that the levels of Tim-3 on CD4+ T cells and CD8+ T cells exhibited different expression patterns in terms of localization depending on pathological category of prostate cancer and metastasis. Immunohistochemical analysis revealed that positive staining of Tim-3 in prostate cancer but little or no staining of Tim-3 was observed in benign prostate hyperplasia epithelium. Tim-3 may affect the development and progression of prostate cancer, which may provide knowledge for using Tim-3 as a novel therapy for effective prostate cancer management.
[Mh] Termos MeSH primário: Receptor Celular 2 do Vírus da Hepatite A/genética
Proteínas de Membrana/genética
Hiperplasia Prostática/genética
Neoplasias da Próstata/genética
[Mh] Termos MeSH secundário: Idoso
Linfócitos T CD4-Positivos/patologia
Linfócitos T CD8-Positivos/patologia
Progressão da Doença
Citometria de Fluxo
Seres Humanos
Masculino
Meia-Idade
Hiperplasia Prostática/patologia
Neoplasias da Próstata/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (Membrane Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317716628


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[PMID]:28671022
[Au] Autor:Ge W; Li J; Fan W; Xu D; Sun S
[Ad] Endereço:1 Department of Paediatrics, Rizhao People's Hospital, Rizhao, China.
[Ti] Título:Tim-3 as a diagnostic and prognostic biomarker of osteosarcoma.
[So] Source:Tumour Biol;39(7):1010428317715643, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Osteosarcoma is the most frequent primary bone tumor that affects adolescents and children. However, diagnostic and prognostic biomarkers for osteosarcoma remain lacking. (Tim-3) T-cell immunoglobulin domain and mucin domain-3, which negatively regulates T cell helper (Th1) cells and affects cytokine expression, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In this study, we evaluated serum soluble Tim-3 level in osteosarcoma patients to explore its diagnostic and prognostic value for this particular malignancy. Serum soluble Tim-3 level was measured with enzyme-linked immunosorbent assay in 120 osteosarcoma patients, 120 benign bone tumors patients and 120 healthy controls, followed by analysis of the correlation with clinic pathological characteristics. Receiver operating curves, Kaplan-Meier curves, and log-rank analyses as well as Cox proportional hazard models were used to evaluate the diagnostic and prognostic significance. Serum solubleTim-3 level was remarkably elevated in osteosarcoma patients. Osteosarcoma patients with larger tumor size, late stages and distant metastases were accompanied with higher levels of Tim-3. ROC/AUC analysis indicated thatTim-3 served as a reliable marker to distinguish healthy participants from Tim-3 patients. Osteosarcoma patients with higher Tim-3 had relatively lower survival. Multivariate analyses for overall survival revealed that high serum soluble Tim-3 level was an independent prognostic factor for osteosarcoma. Furthermore, Tim-3 levels of CD8+ and CD4+ T cells were elevated in peripheral circulation of osteosarcoma patients. Therefore, It was indicated in our research that elevated serum soluble Tim-3 level might be a novel potential diagnostic and prognostic biomarker for osteosarcoma patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/sangue
Receptor Celular 2 do Vírus da Hepatite A/sangue
Osteossarcoma/sangue
Prognóstico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Intervalo Livre de Doença
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Osteossarcoma/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317715643


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[PMID]:28648905
[Au] Autor:Zhou G; Sprengers D; Boor PPC; Doukas M; Schutz H; Mancham S; Pedroza-Gonzalez A; Polak WG; de Jonge J; Gaspersz M; Dong H; Thielemans K; Pan Q; IJzermans JNM; Bruno MJ; Kwekkeboom J
[Ad] Endereço:Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands.
[Ti] Título:Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.
[So] Source:Gastroenterology;153(4):1107-1119.e10, 2017 Oct.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 and CD8 T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. METHODS: We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 and CD4 T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. RESULTS: Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 and CD4 T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 TIL, compared with other CD8 TIL. Compared with TIL that did not express these inhibitory receptors, CD8 and CD4 TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 and CD4 TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. CONCLUSIONS: The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Anticorpos Neutralizantes/farmacologia
Antígenos CD
Antineoplásicos/farmacologia
Carcinoma Hepatocelular/tratamento farmacológico
Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores
Imunoterapia/métodos
Neoplasias Hepáticas/tratamento farmacológico
Linfócitos do Interstício Tumoral/efeitos dos fármacos
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Linfócitos T/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antígenos CD/imunologia
Antígenos CD/metabolismo
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Antígeno CTLA-4/antagonistas & inibidores
Antígeno CTLA-4/imunologia
Antígeno CTLA-4/metabolismo
Carcinoma Hepatocelular/imunologia
Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Técnicas de Cocultura
Citocinas/metabolismo
Receptor Celular 2 do Vírus da Hepatite A/imunologia
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Seres Humanos
Neoplasias Hepáticas/imunologia
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Ativação Linfocitária/efeitos dos fármacos
Linfócitos do Interstício Tumoral/imunologia
Linfócitos do Interstício Tumoral/metabolismo
Receptor de Morte Celular Programada 1/imunologia
Receptor de Morte Celular Programada 1/metabolismo
Transdução de Sinais/efeitos dos fármacos
Linfócitos T/imunologia
Linfócitos T/metabolismo
Evasão Tumoral/efeitos dos fármacos
Microambiente Tumoral
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antibodies, Neutralizing); 0 (Antigens, CD); 0 (Antineoplastic Agents); 0 (CD223 antigen); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (Cytokines); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28637584
[Au] Autor:Zhang T; Yuan X; Liu C; Li Y; Liu H; Li L; Ding K; Wang T; Wang H; Shao Z; Fu R
[Ad] Endereço:The Department of Hematology, General Hospital of Tianjin Medical University, Tianjin, PR China.
[Ti] Título:Decreased TIM-3 expression of peripheral blood natural killer cells in patients with severe aplastic anemia.
[So] Source:Cell Immunol;318:17-22, 2017 Aug.
[Is] ISSN:1090-2163
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Severe aplastic anemia (SAA) is an autoimmune disease characterized by severe pancytopenia and bone marrow failure. In our previous studies, we found natural killer (NK) cells were aberrant in SAA patients. T cell immunoglobulin mucin-3 (TIM-3), an important regulator of immunity, is widely detected on NK cells and may contribute as a marker of activation and maturation of NK cells. In this study, we found that SAA untreated patients had lower TIM-3 expression on NK cells and CD56 NK subsets compared with normal controls, and were correlated with the severity of pancytopenia of SAA. After immunosuppressive therapy (IST), TIM-3 expression recovered to normal level. Moreover, the TIM-3 mRNA levels in NK cells significantly increased in SAA remission patients after IST. We inferred that low expression of TIM-3 on NK cells might lead to NK cells dysfunction and involve in the progress of bone marrow failure in SAA.
[Mh] Termos MeSH primário: Anemia Aplástica/imunologia
Células Sanguíneas/imunologia
Regulação Neoplásica da Expressão Gênica
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Células Matadoras Naturais/imunologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Diferenciação Celular
Criança
Progressão da Doença
Regulação para Baixo
Feminino
Receptor Celular 2 do Vírus da Hepatite A/genética
Seres Humanos
Ativação Linfocitária
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE



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