Intrapulmonary administration of CCL21 gene-modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell carcinoma.

Abstract

The antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-gamma, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-beta, prostaglandin E(2)) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-gamma compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival by >7 weeks in CC-10 TAg mice. Both innate natural killer and specific T-cell antitumor responses significantly increased following DC-AdCCL21 therapy. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 in regulation of tumor immunity and genetic immunotherapy for lung cancer.

• Authors: Seok-Chul Yang, Raj K Batra, Sven Hillinger, Karen L Reckamp, Robert M Strieter, Steven M Dubinett, Sherven Sharma
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 6 Pg. 3205-13 (Mar 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16540672 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Viral, Tumor
• Ccl21c protein, mouse
• Chemokine CCL21
• Chemokines, CC
• Cytokines

Topics

• Adenocarcinoma, Bronchiolo-Alveolar (genetics, immunology, therapy)
• Animals
• Antigens, Viral, Tumor (immunology)
• Chemokine CCL21
• Chemokines, CC (genetics, immunology)
• Cytokines (immunology, metabolism)
• Dendritic Cells (immunology, physiology)
• Genetic Therapy (methods)
• Immunotherapy, Adoptive (methods)
• Lung Neoplasms (genetics, immunology, therapy)
• Mice
• Mice, Transgenic
• T-Lymphocytes (immunology)