Potential involvement of monocyte chemoattractant protein (MCP)-1/CCL2 in IL-4-mediated tumor immunity through inducing dendritic cell migration into the draining lymph nodes

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Abstract

We previously observed that IL-4 gene transduction into a mouse colon 26 adenocarcinoma cell line abrogated its tumorigenicity due to the generation of anti-tumor CTL. DEC-205- and CD11c-double positive cells were increased in the lymph nodes of mice injected with IL-4-transfected cells between 2 and 3 days after the tumor injection, compared with those injected with parental cells. Most of these double positive cells expressed CD86 antigen. Among the chemokines with chemotactic activities against dendritic cells, monocyte chemoattractant protein (MCP)-1/CCL2, ABCD-1/CCL22, and liver and activation-regulated chemokine (LARC)/CCL20 gene expression was enhanced no later than 3 days after the tumor injection, in the draining lymph nodes of IL-4-transfected cell bearing mice. Moreover, gene expression of the receptor for MCP-1/CCL2, CCR2, was enhanced in the draining lymph nodes of the mice injected with IL-4-transfected cells, and most DEC-205-positive cells in the lymph nodes expressed CCR2. Finally, the administration of anti-MCP-1/CCL2 antibodies retarded the rate of tumor regression in mice injected with IL-4-tranfected cells, concomitantly with a decrease in DEC-205- and CD11c-double positive cell number in the draining lymph nodes. Thus, locally produced MCP-1/CCL2 may be responsible for IL-4-mediated tumor rejection presumably based on the induction of dendritic cell migration into the draining lymph nodes.

Introduction

Accumulating evidence indicates that potent antigen-presenting cells, dendritic cells, prime CD8+ CTL capable of recognizing and killing tumor cells in an antigen-dependent manner in the secondary lymphoid organs, particularly draining lymph nodes, thereby inducing specific tumor immunity [1], [2]. Hence, the draining lymph node is a first-line sentinel site for execution of tumor immunosurveillance. Paradoxically, tumors frequently metastasize to the draining lymph nodes without being rejected and metastasis in the lymph nodes is usually a poor prognostic sign [3]. There may be several reasons for the failure of effective immunosurveillance in the draining lymph nodes. First of all, many tumors expressed too low amount of tumor antigens to induce immune reactions [4]. Alternatively, a reduction in the dendritic cell number or the capacity of the dendritic cells to present antigens [5] may result in the failure of dendritic cells to prime CTLs in the draining lymph nodes. In the latter case, specific immunity can be generated by the improvement of the traffic and functions of dendritic cells.

Chemokines were originally identified as potent chemoattractants for inflammatory cells including neutrophils, eosinophils, and monocytes/macrophages [6]. Subsequent studies have revealed that chemokines have profound effects on immune reactions by regulating trafficking of dendritic cells as well as lymphocytes into lymphoid organs [7]. Dendritic cells are migratory cells which sample antigens in the tissue migrate to the draining lymph nodes, and mature to stimulate T-cell response [8]. Evidence is accumulating that dendritic cells utilize distinct sets of chemokine receptors, depending on the maturation stages. Immature dendritic cells, resident in the tissues, express CCR1, CCR2, CCR4, CCR5, CXCR1, and CXCR4, while mature dendritic cells express a limited set of chemokine receptors, CXCR4 and CCR7 [9], [10], [11], [12], [13]. Moreover, these chemokine receptors are functional in terms of in vitro chemotactic activity [9], [10], [11], [12], [13]. However, it remains to be determined which type of a receptor(s) is actually responsible for dendritic cell migration in vivo in the various types of immune responses.

A mouse colon adenocarcinoma cell line, colon 26, expresses the endogenous murine leukemia virus env protein and is highly immunogenic [14]. Moreover, specific CTLs were generated in the draining lymph nodes rapidly no later than 5 days after the footpad injection of colon 26 cells co-transfected with GM-CSF and CD40 ligand gene [14]. We also previously observed that IL-4 gene transduction into a mouse colon 26 adenocarcinoma cell line abrogated its tumorigenicity with concomitant CTL generation in the draining lymph nodes, when the IL-4-transfected tumor cells were injected s.c. into immunocompetent mice [15]. Since these observations suggested that the dendritic cells migrated to the draining lymph nodes to prime CTLs, we evaluated the distribution of dendritic cells in the draining lymph nodes. We observed an increase in the number of phenotypically mature dendritic cells in the draining lymph nodes of mice injected with IL-4-transfected cells, compared with those injected with parental cells. Moreover, we herein provide evidence that a chemokine, monocyte chemoattractant protein (MCP)-1/CCL2, was involved in IL-4-mediated tumor rejection based on its capacity to recruit dendritic cells into the draining lymph nodes.

Section snippets

Mice

Pathogen-free, 8- to 9-week-old female BALB/c mice were obtained from Charles River Japan (Yokahama, Japan). IFN-γ-deficient mice, backcrossed to BALB/c mice for more than six generations [15], were kept in our animal facility under specific pathogen-free conditions. Mice weighing between 19 and 23 g were used for the experiments, in compliance with the standards set out in the Guidelines for the care and use of Laboratory Animals, at the Takara-machi campus of Kanazawa University.

Cell line

A murine

Accumulation of DEC-205-positive cells in the draining lymph nodes of mice injected with IL-4-transfected cells

In our previous study, we demonstrated that specific CTL activity against colon 26 cells was generated in the draining lymph nodes of mice injected with IL-4-transfected colon 26 cells but not parental cells [15]. These observations suggested the presence of functionally competent antigen-presenting cells, dendritic cells, in the draining lymph nodes of mice injected with IL-4-transfected cells. This assumption prompted us to perform an immunohistochemical analysis using DEC-205 antibody [21]

Discussion

We previously provided evidence that the injection of IL-4-transfected cells induced the generation of tumor-specific CTLs in the draining lymph nodes [15]. Specific CTL generation requires a sufficient number of antigen-presenting cells in the draining lymph nodes of the tumor-bearing mice [1], [2]. We also observed that DEC-205- and CD11c-double positive cells were increased significantly in the draining lymph nodes of mice injected with IL-4-transfected cell. Most of these DEC-205- and

Acknowledgments

We would like to express our gratitude to Dr. Joost J. Oppenheim for his critical review of the manuscript. We would like to thank Dr. Yuko Ishida (Division of Environmental Sciences, Forensic and Environmental Medicine, Graduate School of Medicine, Kanazawa University) for her technical assistance in immunohistochemical analysis. This work is supported in part by the grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japanese Government and the Osaka Cancer

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