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-Induced Monocyte-Derived Dendritic Cells and NK Cells in Priming CD8+ T Cell Responses against Human Tumor Antigens1
Units of
*
Immunotherapy of Human Tumors and
Immunohematology and Blood Bank, Istituto Nazionale Tumori, Milan, Italy; and
Section of Biology and Genetics of Animal Viruses, Istituto Superiore di Sanità, Rome, Italy
In the present study we evaluated the role of IFN-
in the generation of dendritic cells (IFN-DCs) with priming activity on CD8+ T lymphocytes directed against human tumor Ags. A 3-day treatment of monocytes, obtained as adherent PBMCs from HLA-A*0201+ healthy donors, with IFN- and GM-CSF led to the differentiation of DCs displaying a semimature phenotype, but promptly inducing CD8+ T cell responses after one in vitro sensitization with peptides derived from melanoma (gp100209–217 and MART-1/Melan-A27–35) and adenocarcinoma (CEA605–613) Ags. However, these features were lost when IFN-DCs were generated from immunosorted CD14+ monocytes. The ability of adherent PBMCs to differentiate into IFN-DCs expressing higher levels of costimulatory molecules and exerting efficient T cell priming capacity was associated with the presence of contaminating NK cells, which underwent phenotypic and functional activation upon IFN- treatment. NK cell boost appeared to be mediated by both direct and indirect (i.e., mediated by IFN-DCs) mechanisms. Experiments performed to prove the role of contaminating NK cells in DC differentiation showed that IFN-DCs generated in the absence of NK were phenotypically less mature and could not efficiently prime antitumor CD8+ lymphocytes. Reciprocally, IFN-DCs raised from immunosorted CD14+ monocytes regained their T cell priming activity when NK cells were added to the culture before IFN- and GM-CSF treatment. Together, our data suggest that the ability of IFN-DCs to efficiently prime anti-tumor CD8+ T lymphocytes relied mostly on the positive cross-talk occurring between DCs and NK cells upon stimulation with IFN-.
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