Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors

Abstract

Fractalkine (CX3CL1) is a unique membrane-bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. The hypothesis of this study is that dendritic cells (DC) genetically modified ex vivo to overexpress fractalkine would enhance the T cell-mediated cellular immune response with a consequent induction of anti-tumor immunity to suppress tumor growth. To prove this hypothesis, established tumors of different mouse cancer cells (B16-F10 melanoma, H-2 b , and Colon-26 colon adenocarcinoma, H-2 d ) were treated with intratumoral injection of bone marrowderived DC that had been modified in vitro with an RGD fiber-mutant adenovirus vector expressing mouse fractalkine (Ad-FKN). In both tumor models tested, treatment of tumor-bearing mice with Ad-FKN-transduced DC gave rise to a significant suppression of tumor growth along with survival advantages in the treated mice. Immunohistochemical analysis of tumors treated with direct injection of Ad-FKN-transduced DC demonstrated that the treatment prompted CD8 + T cells and CD4 + T cells to accumulate in the tumor milieu, leading to activation of immune-relevant processes. Consistent with the finding, the intratumoral administration of Ad-FKN-transduced DC evoked tumor-specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host. In addition, the anti-tumor effect provided by intratumoral injection of Ad-FKN-transduced DC was completely abrogated in CD4 + T cell-deficient mice as well as in CD8 + T cell-deficient mice. These results support the concept that genetic modification of DC with a recombinant fractalkine adenovirus vector may be a useful strategy for cancer immunotherapy protocols.

Fractalkine-Induced MFG-E8 Leads to Enhanced Apoptotic Cell Clearance by Macrophages

“…It is responsible for the recruitment of natural killer cells to the brain during experimental autoimmune encephalitis (31), involved in asthma-associated mast cell chemotaxis (19), and chemotaxis of leukocytes in experimental autoimmune myositis (18). It is also associated with the induction of an antitumor Th 1 response (21,32). Inflammation has been reported to induce NF-κB-dependent CX 3 CL1 upregulation in different tissues, through TNF-α, LPS or advanced glycation endproducts (30,33,34).…”

“…Although CX 3 CL1 upregulation and release have been found to be associated mainly with infections or inflammatory diseases (14)(15)(16)(17)(18)(19)(20), this protein had also been shown to be crucial in normal immune response and in the induction of antitumor cytotoxic T cells (21)(22)(23).…”

OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice

“…EG7-OVA cells were grown in complete RPMI-1640 media containing 0.4 mg/ml G418 (Invitrogen). DCs were generated from mouse bone marrow precursors as previously described (57)(58)(59). DCs prepared from OX40L -/-or CD1d -/-mice were used in some experiments.…”

A Phagocytotic Inducer from Herbal Constituent, Pentagalloylglucose Enhances Lipoplex-Mediated Gene Transfection in Dendritic Cells

“…Conventional DC vaccine therapies have already succeeded to some extent. In addition to these conventional therapies, DC vaccine therapy is expected to be highly effective and to be refined by more efficient lipofection of cytokines, 57) chemokines 58) and tumor-associated antigens (TAAs) using PGG.…”