Loss of New Chemokine CXCL14 in Tumor Tissue Is Associated with Low Infiltration by Dendritic Cells (DC), while Restoration of Human CXCL14 Expression in Tumor Cells Causes Attraction of DC Both In Vitro and In Vivo

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-κB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.

Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?

“…Second, we have recently reported that the lost expression of chemokine CXCL14 in human SCCHN tumors may be associated with decreased attraction of DC to the tumor site and, thus, may also be associated with deficient induction of antitumor immune responses [54]. The important role of CXC14 in attraction of immature DC and DC precursors to normal tissues has been also confirmed by others [67,68].…”

“…It has been recently demonstrated that many tumor cell lines loss the expression of CXCL14 [125]. We and other reported that CXCL14 is a potent chemoattractant for immature DC [54,67] suggesting that loss expression of CXCL14 at the tumor site might be responsible, at least in part, for low attraction of DC and thus deficient initiation of antitumor immune responses.…”

“…For instance, CXCL14 not only stimulates DC maturation and activation [54], but is able to up-regulate expression of antigen-processing machinery components in DC and thus, antigen processing and presentation to T cells (Shurin, unpublished data). Similar results were reported for APC function of macrophages: macrophages generated from bone marrow progenitor cells in vitro with M-CSF were defective in APC function, while macrophages generated in the presence of the CC chemokines Lkn-1, MIP-1α, and RANTES together with M-CSF exhibited much stronger APC function [126].…”

“…Historically, immunohistochemical strategies were the most common and widely used [51][52][53] in spite of a very limited quantitative applicability. For example, using this approach, loss of expression of CXCL14 in HNSCC has been recently reported [54]. Together with in situ PCR on tumor specimens, immunohistochemistry allow evaluation of cytokine distribution in tumor mass and co-localization with specific cell subtypes.…”

Platelets as a Novel Source of Pro-Inflammatory Chemokine CXCL14

“…CXCL14 is further expressed in several immune cell types, such as immature dendritic cells (iDCs), monocyte-derived dendritic cells (DCs), activated B-cells and activated isolated human monocytes [14-16]. CXCL14 is known to act as a chemotactic agent for human B-cells, THP-1 cells, activated human natural killer cells (NKs), human and murine iDCs as well as human monocytes [12, 13, 16-19]. Cutaneous CXCL14 is involved in the recruitment of CD14 + DC precursors and in driving their differentiation into Langerhans cells [13].…”