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rdf:type |
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lifeskim:mentions |
umls-concept:C0023467,
umls-concept:C0026809,
umls-concept:C0031437,
umls-concept:C0085358,
umls-concept:C0205221,
umls-concept:C0392674,
umls-concept:C1332717,
umls-concept:C1413244,
umls-concept:C1425514,
umls-concept:C1706438,
umls-concept:C2698600
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pubmed:issue |
17
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pubmed:dateCreated |
2011-4-29
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pubmed:abstractText |
Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8(+) T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-?, TNF-?, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8(+) T cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing-albeit not eliminating-both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Galectins,
http://linkedlifedata.com/resource/pubmed/chemical/Havcr2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Pdcd1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Programmed Cell Death 1 Receptor,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Virus,
http://linkedlifedata.com/resource/pubmed/chemical/galectin 9, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1528-0020
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pubmed:author |
pubmed-author:AndersonAna CAC,
pubmed-author:AzumaMiyukiM,
pubmed-author:BlazarBruce RBR,
pubmed-author:HirashimaMitsuomiM,
pubmed-author:KuchrooVijay KVK,
pubmed-author:MungerMeghan EME,
pubmed-author:MunnDavid HDH,
pubmed-author:MurphyWilliam JWJ,
pubmed-author:VeenstraRachelle GRG,
pubmed-author:WeigelBrenda JBJ,
pubmed-author:ZhouQingQ
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pubmed:issnType |
Electronic
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pubmed:day |
28
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pubmed:volume |
117
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4501-10
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21385853-Animals,
pubmed-meshheading:21385853-Antibodies, Monoclonal,
pubmed-meshheading:21385853-Antigens, Surface,
pubmed-meshheading:21385853-Apoptosis Regulatory Proteins,
pubmed-meshheading:21385853-CD8-Positive T-Lymphocytes,
pubmed-meshheading:21385853-Galectins,
pubmed-meshheading:21385853-Gene Expression,
pubmed-meshheading:21385853-Genes, Lethal,
pubmed-meshheading:21385853-Immunophenotyping,
pubmed-meshheading:21385853-Leukemia, Myeloid, Acute,
pubmed-meshheading:21385853-Liver,
pubmed-meshheading:21385853-Mice,
pubmed-meshheading:21385853-Mice, Inbred C57BL,
pubmed-meshheading:21385853-Mice, Knockout,
pubmed-meshheading:21385853-Phenotype,
pubmed-meshheading:21385853-Programmed Cell Death 1 Receptor,
pubmed-meshheading:21385853-Receptors, Virus,
pubmed-meshheading:21385853-Signal Transduction
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pubmed:year |
2011
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pubmed:articleTitle |
Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
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pubmed:affiliation |
Masonic Cancer Center and Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, Kagawa University, Kagawa, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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