Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer.
The antitumor activity of IFN-alpha is well established. However, the role of the plasmacytoid dendritic cell (PDC), the major producer of IFN-alpha upon viral infection, in tumor biology is unknown. We sought to study the presence and function of PDC in a human solid tumor. Here, we demonstrate that PDCs infiltrate tumor tissue of patients with head and neck squamous cell carcinoma (HNSCC). Functional activity of PDC was examined by using CpG motif containing oligonucleotides, a defined microbial stimulus for PDCs (recognized via toll-like receptor 9). We found that HNSCC diminished the ability of PDC to produce IFN-alpha in response to CpG motif containing oligonucleotide. Tumor-induced down-regulation of toll-like receptor 9 was identified as one mechanism likely contributing to impaired PDC function within the tumor environment. In tumor-draining lymph nodes, suppression of CpG-induced IFN-alpha production was less pronounced than in single-cell suspensions of primary tumor tissue. In these lymph nodes, CpG-induced IFN-alpha production was associated with increased levels of interferon-induced protein 10 and IFN-gamma and activation of CD4 and CD8 T cells. These results show for the first time the presence of PDCs in human solid tumor tissue and that tumors suppress the capacity of PDCs to produce IFN-alpha. PDCs, which in the absence of appropriate stimulation are reported to promote regulatory CD8 T cells, may contribute to an impaired T-cell-mediated immune response in HNSCC.
Hartmann
Evelyn
E
Department of Internal Medicine and Division of Clinical Pharmacology, Ludwig-Maximilians University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany.
Wollenberg
Barbara
B
Rothenfusser
Simon
S
Wagner
Moritz
M
Wellisch
Daniela
D
Mack
Brigitte
B
Giese
Thomas
T
Gires
Olivier
O
Endres
Stefan
S
Hartmann
Gunther
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D016898:Interferon-alpha; D009841:Oligonucleotides