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Shigeki Chiba,
Muhammad Baghdadi,
Hisaya Akiba,
Hironori Yoshiyama,
Ichiro Kinoshita,
Hirotoshi Dosaka-Akita,
Yoichiro Fujioka,
Yusuke Ohba,
Jacob V Gorman,
John D Colgan,
Mitsuomi Hirashima,
Toshimitsu Uede,
Akinori Takaoka,
Hideo Yagita,
Masahisa Jinushi
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ABSTRACT: 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.
Nature Immunology 07/2012; 13(9):832-42. · 26.01 Impact Factor
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ABSTRACT: 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.
PLoS ONE 01/2012; 7(6):e39607. · 4.09 Impact Factor
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ABSTRACT: 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.
American journal of cancer research. 01/2012; 2(5):529-39.
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ABSTRACT: Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
Cancer Research 11/2011; 72(1):56-65. · 7.86 Impact Factor
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ABSTRACT: Recent evidence has unveiled the critical role of tumor cells with stem cell activities in tumorigenicity and drug resistance, but how tumor microenvironments regulate cancer stem/initiating cells (CSCs) remains unknown. We clarified the role of tumor-associated macrophages (TAMs) and their downstream factor milk-fat globule-epidermal growth factor-VIII (MFG-E8) in the regulation of CSC activities. Bone marrow chimeric systems and adoptive cell transfers elucidated the importance of MFG-E8 from TAMs in conferring to CSCs with the ability to promote tumorigenicity and anticancer drug resistance. MFG-E8 mainly activates signal transducer and activator of transcription-3 (Stat3) and Sonic Hedgehog pathways in CSCs and further amplifies their anticancer drug resistance in cooperation with IL-6. Thus, the pharmacological targeting of key factors derived from tumor-associated inflammation provides a unique strategy to eradicate therapy-resistant tumors by manipulating CSC activities.
Proceedings of the National Academy of Sciences 07/2011; 108(30):12425-30. · 9.68 Impact Factor
