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1.  Induction of Macrophage-Like Immunosuppressive Cells from Mouse ES Cells That Contribute to Prolong Allogeneic Graft Survival 
PLoS ONE  2014;9(10):e111826.
Recent progress in regenerative medicine has enabled the utilization of pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) as a donor resource for transplantation. However, immune suppression is still needed when the donor-recipient combination is allogeneic. Protection of ESCs-derived grafts from host immune response might be achieved thought the utilization of immunosuppressive cells generated from ESCs. In the present study, we show that a certain fraction of immunosuppressive cells can be generated from ESCs and help to suppress immune response against allogeneic grafts. ESCs-derived suppressor cells (ES-SCs) resembled macrophages in terms of cell surface molecule and gene expressions. Furthermore, gene expression analysis including microarray showed that ES-SCs have M1/M2 hybrid phenotype with high expression of genes correlated to immunosuppression of T cell response. Indeed, ES-SCs were effective to block allogeneic T cell proliferation in a nitric oxide-dependent manner, and prolonged the survival of ESCs-derived embryoid bodies or cardiomyocytes grafts transplanted into mouse kidney capsule. Thus, we consider the potential use of these ESCs-derived macrophage-like immunosuppressive cells as cellular therapies to promote long-term graft survival in future therapies.
doi:10.1371/journal.pone.0111826
PMCID: PMC4214817  PMID: 25356669
2.  The impact of the TIM gene family on tumor immunity and immunosuppression 
Tumor immunoevasion is an advanced phase of cancer immunosurveillance in which tumor cells acquire the ability to circumvent host immune systems and exploit protumorigenic inflammation. T-cell immunoglobulin mucin (TIM) gene family members have emerged as critical checkpoint proteins that regulate multiple immune response phases and maintain immune homeostasis. Accumulating evidence demonstrates that tumor cells exploit TIM gene family members to evade immunosurveillance, whereas TIM gene family members facilitate the prevention of inflammation-related tumor progression. Thus, a comprehensive analysis to clarify the relative contributions of TIM gene family members in tumor progression may elucidate immunosurveillance systems in cancer patients.
doi:10.1038/cmi.2013.57
PMCID: PMC4002149  PMID: 24336162
antitumor immunity; immunoevasion; immunosurveillance; TIM; tumorigenic inflammation
4.  Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1 
Nature immunology  2012;13(9):832-842.
The mechanisms by which tumor microenvironments modulate nucleic acid–mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.
doi:10.1038/ni.2376
PMCID: PMC3622453  PMID: 22842346
5.  Regulation of cancer stem cell activities by tumor-associated macrophages 
Recent studies revealed that tumor-associated macrophages play a decisive role in the regulation of tumor progression by manipulating tumor oncogenesis, angiogenesis and immune functions within tumor microenvironments. However, the role of cancer stem cells in the tumorigenic activities of tumor-associated macrophages during the course of transformation and treatment remains largely unknown. Recent studies have clarified the functional aspects of tumor-associated macrophages in the regulation of the tumorigenic activities and anticancer drug responsiveness of cancer stem cells through complex networks formed by distinct sets of cytokines, chemokines and growth factors. In this article we discuss recent advances and future perspectives regarding the molecular interplay between cancer stem cells and tumor-associated macrophages and provide future perspective about the therapeutic implication against treatment-resistant variants of cancer.
PMCID: PMC3433107  PMID: 22957305
Cancer stem cells; tumor associated macrophages; tumor microenvironments; MFG-E8; IL-6; TIM-3; M-CSF
6.  MFG-E8 Regulates the Immunogenic Potential of Dendritic Cells Primed with Necrotic Cell-Mediated Inflammatory Signals 
PLoS ONE  2012;7(6):e39607.
Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity.
doi:10.1371/journal.pone.0039607
PMCID: PMC3382463  PMID: 22761839

Results 1-6 (6)