title: 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, 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-gamma, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor beta and prostaglandin E(2). DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-gamma, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-gamma significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.
authors.affiliation: Department of Medicine, University of California Los Angeles Lung Cancer Research Program and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, 90095, USA.
authors.forename: Seok-Chul
authors.initials: SC
authors.lastname: Yang
authors.forename: Sven
authors.initials: S
authors.lastname: Hillinger
authors.forename: Karen
authors.initials: K
authors.lastname: Riedl
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Kimberly
authors.initials: K
authors.lastname: Atianzar
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Kuo
authors.forename: Brian
authors.initials: B
authors.lastname: Gardner
authors.forename: Raj K
authors.initials: RK
authors.lastname: Batra
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017252:CD3 Complex; D019496:Cancer Vaccines; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D016207:Cytokines; D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone