Hartmann Evelyn, Wollenberg Barbara, Rothenfusser Simon, Wagner Moritz, Wellisch Daniela, Mack Brigitte, Giese Thomas, Gires Olivier, Endres Stefan, Hartmann Gunther
Department of Internal Medicine and Division of Clinical Pharmacology, Ludwig-Maximilians University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany.
Cancer Res. 2003 Oct 1;63(19):6478-87.
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.
干扰素-α的抗肿瘤活性已得到充分证实。然而，浆细胞样树突状细胞（PDC）作为病毒感染时干扰素-α的主要产生者，在肿瘤生物学中的作用尚不清楚。我们试图研究PDC在人类实体瘤中的存在情况及其功能。在此，我们证明PDC浸润头颈部鳞状细胞癌（HNSCC）患者的肿瘤组织。通过使用含CpG基序的寡核苷酸（一种针对PDC的特定微生物刺激物，通过Toll样受体9识别）来检测PDC的功能活性。我们发现，HNSCC降低了PDC对含CpG基序寡核苷酸产生干扰素-α的能力。肿瘤诱导的Toll样受体9下调被确定为可能导致肿瘤环境中PDC功能受损的一种机制。在肿瘤引流淋巴结中，CpG诱导的干扰素-α产生的抑制作用不如在原发性肿瘤组织的单细胞悬液中明显。在这些淋巴结中，CpG诱导的干扰素-α产生与干扰素诱导蛋白10和干扰素-γ水平升高以及CD4和CD8 T细胞活化相关。这些结果首次表明人类实体瘤组织中存在PDC，且肿瘤会抑制PDC产生干扰素-α的能力。据报道，在缺乏适当刺激的情况下，PDC会促进调节性CD8 T细胞，这可能导致HNSCC中T细胞介导的免疫反应受损。
