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Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.

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 therapeuti... Full description

Journal Title: Cancer research December 1, 2010, Vol.70(23), pp.9599-9610
Main Author: Kujawski, Maciej
Other Authors: Zhang, Chunyan , Herrmann, Andreas , Reckamp, Karen , Scuto, Anna , Jensen, Michael , Deng, Jiehui , Forman, Stephen , Figlin, Robert , Yu, Hua
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1538-7445 ; DOI: 10.1158/0008-5472.CAN-10-1293
Link: http://search.proquest.com/docview/816792109/?pq-origsite=primo
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title: Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.
format: Article
creator:
  • Kujawski, Maciej
  • Zhang, Chunyan
  • Herrmann, Andreas
  • Reckamp, Karen
  • Scuto, Anna
  • Jensen, Michael
  • Deng, Jiehui
  • Forman, Stephen
  • Figlin, Robert
  • Yu, Hua
subjects:
  • Animals–Therapeutic Use
  • Antineoplastic Agents–Immunology
  • Cd8-Positive T-Lymphocytes–Metabolism
  • Cell Line, Tumor–Transplantation
  • Cell Proliferation–Immunology
  • Combined Modality Therapy–Metabolism
  • Dendritic Cells–Methods
  • Female–Therapeutic Use
  • Immunotherapy, Adoptive–Immunology
  • Indoles–Metabolism
  • Lymphocytes, Tumor-Infiltrating–Immunology
  • Male–Pathology
  • Melanoma, Experimental–Therapy
  • Mice–Therapeutic Use
  • Mice, Inbred Balb C–Antagonists & Inhibitors
  • Mice, Inbred C57bl–Deficiency
  • Mice, Knockout–Genetics
  • Pyrroles–Immunology
  • Stat3 Transcription Factor
ispartof: Cancer research, December 1, 2010, Vol.70(23), pp.9599-9610
description: 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. Cancer Res; 70(23); 9599-610. [copy ]2010 AACR.
language: eng
source:
identifier: E-ISSN: 1538-7445 ; DOI: 10.1158/0008-5472.CAN-10-1293
fulltext: fulltext
issn:
  • 15387445
  • 1538-7445
url: Link


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titleTargeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.
creatorKujawski, Maciej ; Zhang, Chunyan ; Herrmann, Andreas ; Reckamp, Karen ; Scuto, Anna ; Jensen, Michael ; Deng, Jiehui ; Forman, Stephen ; Figlin, Robert ; Yu, Hua
contributorKujawski, Maciej (correspondence author) ; Kujawski, Maciej (record owner)
ispartofCancer research, December 1, 2010, Vol.70(23), pp.9599-9610
identifierE-ISSN: 1538-7445 ; DOI: 10.1158/0008-5472.CAN-10-1293
subjectAnimals–Therapeutic Use ; Antineoplastic Agents–Immunology ; Cd8-Positive T-Lymphocytes–Metabolism ; Cell Line, Tumor–Transplantation ; Cell Proliferation–Immunology ; Combined Modality Therapy–Metabolism ; Dendritic Cells–Methods ; Female–Therapeutic Use ; Immunotherapy, Adoptive–Immunology ; Indoles–Metabolism ; Lymphocytes, Tumor-Infiltrating–Immunology ; Male–Pathology ; Melanoma, Experimental–Therapy ; Mice–Therapeutic Use ; Mice, Inbred Balb C–Antagonists & Inhibitors ; Mice, Inbred C57bl–Deficiency ; Mice, Knockout–Genetics ; Pyrroles–Immunology ; Stat3 Transcription Factor
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descriptionAdoptive 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. Cancer Res; 70(23); 9599-610. [copy ]2010 AACR.
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titleTargeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.
authorKujawski, Maciej ; Zhang, Chunyan ; Herrmann, Andreas ; Reckamp, Karen ; Scuto, Anna ; Jensen, Michael ; Deng, Jiehui ; Forman, Stephen ; Figlin, Robert ; Yu, Hua
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