Elsevier

Clinical Immunology

Volume 130, Issue 3, March 2009, Pages 322-330
Clinical Immunology

Galectin-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice

https://doi.org/10.1016/j.clim.2008.09.014Get rights and content

Abstract

Galectin-9 (Gal-9) inhibits the metastasis of tumor cells by blocking their adhesion to endothelium and the extracellular matrix. In this study, we addressed the involvement of Gal-9 in anti-tumor activity. Gal-9 significantly prolonged the survival of B16F10 melanoma-bearing mice. Gal-9 increased the numbers of NK cells, CD8 T cells and macrophages in tumor-bearing mice. Gal-9-mediated anti-tumor activity was not induced in NK cell-, macrophage- and CD8 T cell-depleted mice. NK cells from Gal-9-treated mice, compared to PBS-treated mice, exhibited significantly higher cytolytic activity. Co-culture of naïve NK cells with macrophages from Gal-9-treated mice resulted in enhanced NK activity, although Gal-9 itself did not enhance the NK activity. We also found that Ly-6C+CD11b+F4/80+ macrophages with plasmacytoid cell (pDC)-like phenotypes (PDCA-1 and B220) were responsible for the enhanced NK activity. These results provide evidence that Gal-9 promotes NK cell-mediated anti-tumor activity by expanding unique macrophages with a pDC-like phenotype.

Introduction

Galectin-9 (Gal-9), a β-galactoside binding lectin, modulates a variety of biological functions, such as cell aggregation, adhesion and apoptosis of tumor cells, similar to other galectins [1], [2], [3]. It was first identified as an eosinophil chemoattractant that was associated with eosinophil survival [4], [5], [6], [7]. Gal-9 is localized in the cytoplasm and on the cell surface of tumor cells, and appears to be released from tumor cells [8], [9]. We previously described that high Gal-9 expression in tumor cells was closely associated with reduced metastasis and low recurrence in patients with malignant melanoma [10] and breast cancer [11]. In addition, Gal-9 suppressed the metastasis of both B16F10 and Colon26 cells by inhibiting the binding of both hyaluronic acid to CD44 and vascular cell adhesion molecule-1 (VCAM-1) to very late antigen-4 (VL-4) [12]. These results led us to hypothesize that Gal-9 may also exhibit anti-tumor activity in tumor-bearing hosts.

We recently found that Gal-9 induces the maturation of human dendritic cells (DC) from immature DCs [13], and that it also stimulates innate immune cells, such as monocytes and DCs, to secrete a small level of TNF-α in mouse and human systems through Gal-9–Tim-3 interactions [14]. It has been shown that DCs, monocytes and macrophages are required for optimal NK-cell responses [15]. Thus, it is possible that Gal-9 exerts anti-tumor activity by promoting innate immunity.

The purpose of the present study is to show that Gal-9 induces the accumulation of unique macrophages that express a plasmacytoid DC (pDC)-like phenotype by which NK activity is enhanced in tumor-bearing hosts.

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Mice, cell lines and reagents

Female C57BL/6 mice (6 to 8 weeks old) were purchased from Japan SLC (Hamamatsu, Japan). All experimental procedures were approved by the animal care and use committee, conforming to the guidelines for animal experiments at Kagawa University. B16F10 melanoma cells and Yac-1 cells were provided by the Cell Resource Center for Biomedical Research, Tohoku University. Cells were grown in RPMI-1640 medium (Sigma, St. Louis, MO) supplemented with 10% (v/v) heat-inactivated FBS (JRH Biosciences,

Gal-9 prolongs the survival of B16F10-bearing mice

We first performed experiments to clarify if Gal-9 demonstrates anti-tumor activity in vivo. B16F10 cells were inoculated into the peritoneal cavities of C57BL6/J mice. Intraperitoneal Gal-9 treatment was started at 0.5 h after the inoculation, and continued every day until day 19. Although all the PBS-treated B16F10-bearing mice (n = 5) died by day 23 after the inoculation, Gal-9 treatment dramatically prolonged the survival of B16F10-bearing mice (Fig. 1).

NK cells and macrophages are involved in Gal-9-mediated anti-tumor activity

To determine the mechanisms for the

Discussion

We have shown here that Gal-9 treatment prolongs the survival of B16F10-bearing mice, although Gal-9 itself does not induce apoptosis of B16F10 cells [12]. We have also found that NK cells and CD8+ T cells play critical roles in Gal-9-mediated anti-tumor activity. Our results are consistent with many reports showing that NK cells and CD8+ T cells are involved with anti-tumor activity in B16F10-bearing mice [20], [21], [22].

It is quite reasonable that CD8+ T cells are involved with anti-tumor

Acknowledgments

We thank Dr. Aya Yokota for technical assistance with cell sorting. This work was supported, in part, by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. Part of this work was performed in the Division of Animal Experiment and Division of Research Instrument and Equipment, Life Science Research Center, Institute of Research Promotion, Kagawa University.

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