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

Abstract

To achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, genemodified 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-␥, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor ␤ and prostaglandin E 2 . DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-␥, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-␥ significantly reduced the antitumor efficacy of DCAdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.

CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model

“…33,34 Furthermore, intratumoral injection of DC transduced with CCL21 also led to systemic TH1-polarized anti-tumor immunity. 35,36 Qin et al 37 have recently demonstrated in a mouse tumor model for prostate cancer that immunogenicity of a multiepitope DNA vaccine encoding prostate-tumor-associated antigens can be enhanced by a CCL21/prostate antigenfusion gene.…”

CCL19 reduces tumour burden in a model of advanced lung cancer

“…For flow cytometric experiments, two or three fluorochromes (PE, FITC, and Tri-color; PharMingen) were used to gate on the CD3 T lymphocytes in the percol purified leucocyte populations from tumour nodules as described previously (Yang et al, 2004). Dendritic cells were defined as the double-stained CD11c þ DEC205 þ bright populations within the purified leucocyte populations from the tumour nodules.…”

Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication

“…Using adenoviral gene transfer, CCL21 was expressed in tumor-associated antigen -pulsed dendritic cell. Treatment of tumor-bearing mice with these genetically altered dendritic cells resulted in tumor growth inhibition and remission in some of the experimental tumors (3,6). However, in these various experimental tumor models, the utilization of CCL21 as a protein, even at a very high dosage or in combination with dendritic cell -based and DNA-based vaccines (5 -8), resulted in temporal remission of tumors or in their complete obliteration in 20% to 60% of experimental animals.…”