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

• Published in: Clinical cancer research 2004-04, Vol.10 (8), p.2891-2901
• Main Authors: YANG, Seok-Chul, HILLINGER, Sven, STRIETER, Robert M, DUBINETT, Steven M, SHARMA, Sherven, RIEDL, Karen, LING ZHANG, LI ZHU, MIN HUANG, ATIANZAR, Kimberly, KUO, Brian Y, GARDNER, Brian, BATRA, Raj K
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cancer Vaccines; CD3 Complex - biosynthesis; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Chemokine CCL21; Chemokines, CC - biosynthesis; Cytokines - biosynthesis; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dinoprostone - metabolism; Enzyme-Linked Immunosorbent Assay; Fibroblasts - metabolism; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Immunoenzyme Techniques; Immunotherapy - methods; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; T-Lymphocytes - metabolism; Time Factors; Transforming Growth Factor beta - metabolism; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-03-0380

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 10 6 DC-AdCCL21 intratumorally (7–10 ng/ml/10 6 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 E 2 . 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.