Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity

Seok Chul Yang, Sven Hillinger, Karen Riedl, Ling Zhang, Li Zhu, Min Huang, Kimberly Calica Atianzar, Brian Y. Kuo, Brian Gardner, Raj K. Batra, Robert M. Strieter, Steven M. Dubinett, Sherven Sharma

Research output: Contribution to journalArticle

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Abstract

To achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, gene-modified murine bone marrow-derived dendritic cells (DC) was used in a murine lung cancer model. To attract mature host DC and activated T cells at the tumor site, the DC were transduced with an adenoviral vector expressing secondary lymphoid tissue chemokine (CCL21/SLC). Sixty percent of the mice treated with 106 DC-AdCCL21 intratumorally (7-10 ng/ml/106 cells/24 h of CCL21) at weekly intervals for 3 weeks showed complete tumor eradication, whereas only 25% of mice had complete resolution of tumors when mice were treated with fibroblasts expressing CCL21. In contrast only 12% of the mice treated with unmodified or control vector modified DC (DC-AdCV) showed complete tumor eradication. DC-AdCCL21 administration led to increases in the CD4+, CD8+, and CD3+CXCR3+ T cells, as well as DC expressing CD11c + DEC205+. CD4+CD25+ T-regulatory cells infiltrating the tumors were markedly reduced after DC-AdCCL21 therapy. The tumor site cellular infiltrates were accompanied by the enhanced elaboration of granulocyte macrophage colony-stimulating factor, IFN-γ, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor β and prostaglandin E2. DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-γ, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-γ significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)2891-2901
Number of pages11
JournalClinical Cancer Research
Volume10
Issue number8
DOIs
StatePublished - Apr 15 2004

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Dendritic Cells
Immunity
Neoplasms
Chemokine CCL21
Cell- and Tissue-Based Therapy
T-Lymphocytes
Antigen Presentation
Transforming Growth Factors
Neoplasm Antigens
Regulatory T-Lymphocytes
Interleukin-12
Granulocyte-Macrophage Colony-Stimulating Factor
Immunosuppressive Agents
Dinoprostone
Immunotherapy
Lung Neoplasms
Fibroblasts
Bone Marrow

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity. / Yang, Seok Chul; Hillinger, Sven; Riedl, Karen; Zhang, Ling; Zhu, Li; Huang, Min; Atianzar, Kimberly Calica; Kuo, Brian Y.; Gardner, Brian; Batra, Raj K.; Strieter, Robert M.; Dubinett, Steven M.; Sharma, Sherven.

In: Clinical Cancer Research, Vol. 10, No. 8, 15.04.2004, p. 2891-2901.

Research output: Contribution to journalArticle

Yang, SC, Hillinger, S, Riedl, K, Zhang, L, Zhu, L, Huang, M, Atianzar, KC, Kuo, BY, Gardner, B, Batra, RK, Strieter, RM, Dubinett, SM & Sharma, S 2004, 'Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity', Clinical Cancer Research, vol. 10, no. 8, pp. 2891-2901. https://doi.org/10.1158/1078-0432.CCR-03-0380
Yang, Seok Chul ; Hillinger, Sven ; Riedl, Karen ; Zhang, Ling ; Zhu, Li ; Huang, Min ; Atianzar, Kimberly Calica ; Kuo, Brian Y. ; Gardner, Brian ; Batra, Raj K. ; Strieter, Robert M. ; Dubinett, Steven M. ; Sharma, Sherven. / Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 8. pp. 2891-2901.
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abstract = "To achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, gene-modified murine bone marrow-derived dendritic cells (DC) was used in a murine lung cancer model. To attract mature host DC and activated T cells at the tumor site, the DC were transduced with an adenoviral vector expressing secondary lymphoid tissue chemokine (CCL21/SLC). Sixty percent of the mice treated with 106 DC-AdCCL21 intratumorally (7-10 ng/ml/106 cells/24 h of CCL21) at weekly intervals for 3 weeks showed complete tumor eradication, whereas only 25{\%} of mice had complete resolution of tumors when mice were treated with fibroblasts expressing CCL21. In contrast only 12{\%} of the mice treated with unmodified or control vector modified DC (DC-AdCV) showed complete tumor eradication. DC-AdCCL21 administration led to increases in the CD4+, CD8+, and CD3+CXCR3+ T cells, as well as DC expressing CD11c + DEC205+. CD4+CD25+ T-regulatory cells infiltrating the tumors were markedly reduced after DC-AdCCL21 therapy. The tumor site cellular infiltrates were accompanied by the enhanced elaboration of granulocyte macrophage colony-stimulating factor, IFN-γ, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor β and prostaglandin E2. DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-γ, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-γ significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.",
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AU - Zhang, Ling

AU - Zhu, Li

AU - Huang, Min

AU - Atianzar, Kimberly Calica

AU - Kuo, Brian Y.

AU - Gardner, Brian

AU - Batra, Raj K.

AU - Strieter, Robert M.

AU - Dubinett, Steven M.

AU - Sharma, Sherven

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