Abstract
Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squamous epithelium. In this study, we demonstrate that the loss of CXCL14 in HNSCC cells and at HNSCC primary tumor sites was correlated with low or no attraction of dendritic cell (DC) in vitro, and decreased infiltration of HNSCC mass by DC at the tumor site in vivo. Next, we found that recombinant human CXCL14 and CXCL14-positive HNSCC cell lines induced DC attraction in vitro, whereas CXCL14-negative HNSCC cells did not chemoattract DC. Transduction of CXCL14-negative HNSCC cell lines with the human CXCL14 gene resulted in stimulation of DC attraction in vitro and increased tumor infiltration by DC in vivo in chimeric animal models. Furthermore, evaluating the biologic effect of CXCL14 on DC, we demonstrated that the addition of recombinant human CXCL14 to DC cultures resulted in up-regulation of the expression of DC maturation markers, as well as enhanced proliferation of allogeneic T cells in MLR. Activation of DC with recombinant human CXCL14 was accompanied by up-regulation of NF-kappaB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.
Highlights
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The results of the analysis of multiple oral epithelial hyperplasia, and oral squamous cell carcinoma (SCC) specimens suggest that CD83- and CD11cpositive Dendritic Cells (DC) were essentially absent in head and neck squamous cell carcinoma (HNSCC) tissues, and the numbers of CD1a- and S-100-positive DC were markedly lower in the tumor tissues than in oral dysplasia lesions (Fig. 1A)
These data suggest that CXCL14 protein is lost in human HNSCC, which led us to the hypotheses that low infiltration of HNSCC by DC might be associated with the lost expression of certain chemokines (i.e., CXCL14) and whether CXCL14 is chemoattractive for DC
Summary
HNSCC, head and neck squamous cell carcinoma; SCC, squamous cell carcinoma; DC, dendritic cell. It has been shown that many tumor cell lines, including melanoma and colon adenocarcinoma can effectively chemoattract DC in vitro, modulate their phenotype, and eventually, severely damage DC mobility [9] From this point of view, recent reports about loss of certain chemokines in several tumors, including HNSCC, initially sound surprising (10 –12). It is conceivable to hypothesize a new mechanism of tumor escape: loss of certain chemokines by tumor cells results in a low attraction of DC, decreased number of tumor-infiltrating DC and inhibited ability of the immune cells to recognize tumor and initiate specific antitumor immune responses. Patients who had greater numbers of CD1aϩ DC adjacent to tumor had better survival and decreased recurrence rates These suggest that the distribution of DC subsets in HNSCC may reflect the degree of tumor immunity induced in the hostbearing HNSCC. In addition to being potent DC chemoattractant, CXCL14 increased functional activity of DC, which was associated with increased activity of NF-B
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