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Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8⁺ T-Cell Cross-priming but Is Ineffective as a Therapy

Departments of ¹ Immunology, ² Cell Biology and Molecular Physiology, and ³ Dermatology, University of Pittsburgh School of Medicine and ⁴ The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Walter J. Storkus, Departments of Dermatology and Immunology, University of Pittsburgh School of Medicine, W1041 Biomedical Sciences Tower, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-648-9981; Fax: 412-648-8117; E-mail: storkuswj{at}upmc.edu.

Dendritic cells play significant roles in the development and maintenance of antitumor immune responses. Therapeutic recruitment of dendritic cells into the tumor microenvironment has the potential to result in enhanced antitumor T-cell cross-priming against a broad array of naturally processed and presented tumor-associated antigens. We have observed that the treatment of BALB/c mice bearing syngeneic CMS4 sarcomas with the combination of recombinant Flt3 ligand and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for five sequential days is sufficient to optimize the number of tumor-infiltrating dendritic cells (TIDC). However, despite the significant increase in the number of TIDCs, the therapeutic benefit of Flt3 ligand and GM-CSF treatment is minimal. Therapy-associated TIDCs do not exhibit a "suppressed" or "suppressor" phenotype in vitro, and their enhanced numbers in cytokine-treated mice were associated with increased levels of peripheral antitumor CD8⁺ T effector cells and with an augmented population of CD8⁺ tumor-infiltrating lymphocytes (TIL). These data suggest that Flt3 ligand + GM-CSF therapy of murine tumors fails at a mechanistic point that is downstream of specific T-cell priming by therapy-induced TIDCs and the recruitment of these T cells into the tumor microenvironment. Based on the enhanced infiltration of tumors by CD4⁺CD25⁺ TIL in Flt3 ligand + GM-CSF–treated mice, this could reflect the dominant influence of regulatory T cells in situ. (Cancer Res 2006; 66(9): 4895-903)

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