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Am J Pathol ; 179(1): 436-51, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21703422

ABSTRACT

Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209(+) DCs in RCCs was found to be associated with an unfavorable T(H)1 cell balance in the tissue and advanced tumor stages. The CD209(+) DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for T(H)1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC.


Subject(s)
Carcinoma, Renal Cell/immunology , Dendritic Cells/immunology , Kidney Neoplasms/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , Apoptosis , Blotting, Western , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Case-Control Studies , Cell Differentiation , Cell Movement , Cell Proliferation , Chemokines/metabolism , Cross-Priming , Cytokines/metabolism , Dendritic Cells/metabolism , Dendritic Cells/pathology , Endocytosis , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Interleukin-6/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , Phagocytosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Tumor Cells, Cultured
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