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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
23
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pubmed:dateCreated |
2010-12-8
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pubmed:abstractText |
Adoptive cell therapy with engineered T cells to improve natural immune response and antitumor functions has shown promise for treating cancer. However, the requirement for extensive ex vivo manipulation of T cells and the immunosuppressive effects of the tumor microenvironment limit this therapeutic modality. In the present study, we investigated the possibility to circumvent these limitations by engineering Stat3 -deficient CD8(+) T cells or by targeting Stat3 in the tumor microenvironment. We show that ablating Stat3in CD8(+) T cells prior to their transfer allows their efficient tumor infiltration and robust proliferation, resulting in increased tumor antigen-specific T-cell activity and tumor growth inhibition. For potential clinical translation, we combined adoptive T-cell therapy with a Food and Drug Administration-approved tyrosine kinase inhibitor, sunitinib, in renal cell carcinoma and melanoma tumor models. Sunitinib inhibited Stat3 in dendritic cells and T cells and reduced conversion of transferred FoxP3(-) T cells to tumor-associated regulatory T cells while increasing transferred CD8(+) T-cell infiltration and activation at the tumor site, leading to inhibition of primary tumor growth. These data show that adoptively transferred T cells can be expanded and activated in vivo either by engineering Stat3-silenced T cells or by targeting Stat3 systemically with small-molecule inhibitors.
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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 |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1538-7445
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
70
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
9599-610
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pubmed:dateRevised |
2011-3-8
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pubmed:meshHeading |
pubmed-meshheading:21118964-Animals,
pubmed-meshheading:21118964-Antineoplastic Agents,
pubmed-meshheading:21118964-CD8-Positive T-Lymphocytes,
pubmed-meshheading:21118964-Cell Line, Tumor,
pubmed-meshheading:21118964-Cell Proliferation,
pubmed-meshheading:21118964-Combined Modality Therapy,
pubmed-meshheading:21118964-Dendritic Cells,
pubmed-meshheading:21118964-Female,
pubmed-meshheading:21118964-Immunotherapy, Adoptive,
pubmed-meshheading:21118964-Indoles,
pubmed-meshheading:21118964-Lymphocytes, Tumor-Infiltrating,
pubmed-meshheading:21118964-Male,
pubmed-meshheading:21118964-Melanoma, Experimental,
pubmed-meshheading:21118964-Mice,
pubmed-meshheading:21118964-Mice, Inbred BALB C,
pubmed-meshheading:21118964-Mice, Inbred C57BL,
pubmed-meshheading:21118964-Mice, Knockout,
pubmed-meshheading:21118964-Pyrroles,
pubmed-meshheading:21118964-STAT3 Transcription Factor,
pubmed-meshheading:21118964-T-Lymphocytes, Regulatory,
pubmed-meshheading:21118964-Tumor Burden
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pubmed:year |
2010
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pubmed:articleTitle |
Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.
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pubmed:affiliation |
Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, California, USA.
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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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