Dendritic cells respond to nasopharygeal carcinoma cells through annexin A2-recognizing DC-SIGN.

Pin-Zhir Chao,Tin-Jui Hsu,Yun-Tien Lin,Chang-Hao Lai,Chao-Wen Cheng,Chien-Ho Chen,Ming-Shium Hsieh,Wei-Yu Chen,Fei-Peng Lee,Chen-Chung Liao,Ting-Kai Leung,Yung-Feng Lin

doi:10.18632/oncotarget.2700

Abstract

Dendritic cells (DCs) play an essential role in immunity and are used in cancer immunotherapy. However, these cells can be tuned by tumors with immunosuppressive responses. DC-specific intercellular adhesion molecule 3-Grabbing Nonintegrin (DC-SIGN), a C-type lectin expressed on DCs, recognizes certain carbohydrate structures which can be found on cancer cells. Nasopharyngeal carcinoma (NPC) is an epithelial cell-derived malignant tumor, in which immune response remains unclear. This research is to reveal the molecular link on NPC cells that induces the immunosuppressive responses in DCs. In this article, we report identification of annexin A2 (ANXA2) on NPC cells as a ligand for DC-SIGN on DCs. N-linked mannose-rich glycan on ANXA2 may mediate the interaction. ANXA2 was abundantly expressed in NPC, and knockdown of ANXA2 suppressed NPC xenograft in mice, suggesting a crucial role of ANXA2 in NPC growth. Interaction with NPC cells caused DC-SIGN activation in DCs. Consequently DC maturation and the proinflammatory interleukin (IL)-12 production were inhibited, and the immunosuppressive IL-10 production was promoted. Blockage of either DC-SIGN or ANXA2 eliminated the production of IL-10 from DCs. This report suggests that suppression of ANXA2 at its expression or glycosylation on NPC may improve DC-mediated immunotherapy for the tumor.

Highlights

Dendritic cells (DCs) are essential antigenpresenting cells (APCs) recognizing pathogens and tumors
Maturation and cytokine production of Monocyte-derived DCs (MDDCs) were altered by Nasopharyngeal carcinoma (NPC) cells
These data indicated that NPC cells interfered with DC maturation and directed DC cytokine production toward immunosuppressive responses which could be mediated through DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)

Summary

Introduction

Dendritic cells (DCs) are essential antigenpresenting cells (APCs) recognizing pathogens and tumors. DCs can polarize naïve T cells toward Th1 or Th2 pathway, which plays an important role on the way to specify immune responses [2]. Toll-like receptors www.impactjournals.com/oncotarget recognize common pathogen-associated molecules, while C-type lectins are receptors recognizing glycosylated antigens [3]. Toll-like receptors signal to promote DC maturation and induce the production of Th1-polarizing cytokines such as IL-12. Immature DCs strongly express DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209; UniProtKB: Q9NNX6), a kind of C-type lectins [4]. The engagement of DC-SIGN by mannose- or fucose-containing oligosaccharides can lead to an altered Toll-like receptor signaling, resulting in a Th2 response [5, 6]. DC-SIGN signaling increases IL-10 production which is critical for proper immunosuppression [7, 8]

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