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1.  Low expression levels of microRNA-124-5p correlated with poor prognosis in colorectal cancer via targeting of SMC4 
Cancer Medicine  2014;3(6):1544-1552.
A component of polycomb repressor complex 2, enhancer of zeste homolog 2 (EZH2), plays an important role in tumor malignancy and metastasis, while milk fat globule-epidermal growth factor-factor 8 (MFGE8) plays a key role in tumor progression and prognosis. MicroRNAs (miRs) are also critically involved in various physiological and pathological processes. We here evaluated the relationship between overall survival (OS) in colorectal cancer patients and the expression of onco-miRs and miRs, which may target EZH2 and MFGE8. Plasma and formalin-fixed paraffin-embedded (FFPE) samples were obtained from 71 colorectal cancer patients. The expression levels of miRs complementary to EZH2 and MFGE8 mRNA and cancer malignancies were evaluated. The miRs analyzed were as follows: miR-16, miR-21, miR-26a, miR-34a, miR-98, miR-101-3p, miR-101-5p, miR-124-5p (also known as miR-124*), miR-126-3p, miR-126-5p, miR-210, miR-217, and miR-630. The plasma expression levels of MFGE8 in completely resected patients were significantly lower than those in unresectable patients. Lower miR-26a expression levels were correlated with a higher probability of OS. Higher miR-124-5p expression levels in plasma and FFPE samples were correlated with a higher probability of OS. The transfection of mimic miR-124-5p into WiDr and COLO201 cells inhibited the expression of structural maintenance of chromosomes 4 (SMC4) mRNA. Our results indicate that miR-124-5p may target the tumorigenesis gene, SMC4, which suggests that expression levels of miR-124-5p in plasma and FFPE samples; therefore, the expression of MFGE8, miR-26a, and miR-124-5p in plasma may be used as biomarkers to determine the prognosis of colorectal cancer patients.
doi:10.1002/cam4.309
PMCID: PMC4298381  PMID: 25081869
Colorectal cancer; EZH2; MFGE8; miR-124-5p; miR-26a; SMC4
2.  Role of cancer stem cell-associated inflammation in creating pro-inflammatory tumorigenic microenvironments 
Oncoimmunology  2014;3:e28862.
We identify novel mechanisms whereby chemoresistance enables cancer stem cells to create pro-inflammatory tumor microenvironments. Chemoresistant cancer stem cells promote M2 macrophage differentiation through interferon-regulatory factor-5 (IRF5)- and macrophage-colony stimulating factor (M-CSF)-dependent mechanisms and produce various other cell-signaling factors that together fuel inflammation-driven carcinogenesis. These findings clarify a molecular pathway linking cancer “stemness” and pro-tumor inflammation in an immunosuppressive niche.
doi:10.4161/onci.28862
PMCID: PMC4091611  PMID: 25057449
cancer stem cells; chemoresistance; macrophage; inflammation-driven cancer; IRF5
3.  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
5.  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
6.  Regulatory mechanisms of nucleic acid-mediated innate immune responses in the tumor microenvironment 
Oncoimmunology  2012;1(9):1632-1634.
We identified novel mechanisms whereby TIM-3 suppresses innate immunity as induced by nucleic acids. Interaction of TIM-3 with HMGB1 inhibits the recruitment of nucleic acids to the endosomal compartment of dendritic cells, impairing the transduction of innate immune signals. Thus, TIM-3 is an effective target for enhancing the immunogenicity of nucleic acids in the context of cancer therapy.
doi:10.4161/onci.21681
PMCID: PMC3525627  PMID: 23264918
Dendritic cells; HMGB1; innate immunity; nucleic acids; TIM-3
7.  Epstein-Barr Virus (EBV)-associated Gastric Carcinoma 
Viruses  2012;4(12):3420-3439.
The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed.
doi:10.3390/v4123420
PMCID: PMC3528272  PMID: 23342366
EBV; Carcinogenesis; EBV-associated gastric carcinoma; Epithelial; CD21; Methylation; miRNA
8.  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
9.  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
10.  Chronic activation of DNA damage signals causes tumor immune evasion in the chemoresistant niche 
Oncoimmunology  2012;1(3):400-402.
DNA damage responses have been proposed as a gatekeeper to block tumorigenesis. We identify unexpected mechanisms whereby ATM-mediated pathway interacts with NFκB inflammatory cascades, leading to upregulation of integrin-αbβ3 on chemoresistant tumor cells. The integrin-αbβ3 is responsible for impeding tumor-specific immune responses, linking chemoresistant niche with tumor immune evasion.
doi:10.4161/onci.19123
PMCID: PMC3382849  PMID: 22737630
ATM; DNA damage response; Integrin-αvβ3; NFκB; tumor immunity
11.  The role of innate immune signals in antitumor immunity 
Oncoimmunology  2012;1(2):189-194.
Innate immunity serves as a first line of defense against infectious agents, and germ-line-encoded pattern recognition receptors detect stressed and infected cells and elicit potent effector activities that accomplish efficient microbe containment. Recent evidence demonstrates that these pattern-sensing systems are also applicable to the recognition of tumor-derived stress-related factors. In particular, toll-like receptors and cytosolic sensors for DNA and RNA recognition utilize endogenous host elements containing microbial components, danger-associated molecules, and/or nucleic acids to stimulate innate signaling pathways and generate protective immune responses against nascent tumors in animal models and humans. In this review, we describe recent advances and perspectives about antitumor mechanisms and clinical application of innate immune signals and pathways.
doi:10.4161/onci.1.2.18495
PMCID: PMC3376990  PMID: 22720240
antitumor immunity; immunotheropy; NOD-like receptors; RIG-I like helicase; toll-like receptor
12.  Active Immunotherapy Induces Antibody Responses that Target Tumor Angiogenesis 
Cancer research  2010;70(24):10150-10160.
The inhibition of vascular endothelial growth factor (VEGF) signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that anti-angiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and -2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy induced host response that broadly targets the angiogenic network in the tumor microenvironment.
doi:10.1158/0008-5472.CAN-10-1852
PMCID: PMC3057563  PMID: 21159637
Immunotherapy; angiogenesis; GM-CSF; CTLA-4; angiopoietin
13.  Milk fat globule epidermal growth factor–8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms 
The Journal of Experimental Medicine  2009;206(6):1317-1326.
Carcinogenesis reflects the dynamic interplay of transformed cells and normal host elements, but cancer treatments typically target each compartment separately. Within the tumor microenvironment, the secreted protein milk fat globule epidermal growth factor–8 (MFG-E8) stimulates disease progression through coordinated αvβ3 integrin signaling in tumor and host cells. MFG-E8 enhances tumor cell survival, invasion, and angiogenesis, and contributes to local immune suppression. We show that systemic MFG-E8 blockade cooperates with cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy to induce destruction of various types of established mouse tumors. The combination treatments evoke extensive tumor cell apoptosis that is coupled to efficient dendritic cell cross-presentation of dying tumor cells. This linkage engenders potent antitumor effector T cells but inhibits FoxP3+ T reg cells, thereby achieving long-term protective immunity. Collectively, these findings suggest that systemic MFG-E8 blockade might intensify the antitumor activities of existing therapeutic regimens through coordinated cell-autonomous and immune-mediated mechanisms.
doi:10.1084/jem.20082614
PMCID: PMC2715055  PMID: 19433619
14.  T cell Immunoglobulin Mucin Protein (TIM)-4 binds phosphatidylserine and mediates uptake of apoptotic cells 
Immunity  2007;27(6):927-940.
Summary
The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Both TIM-4, expressed on human and mouse macrophages and dendritic cells, and TIM-1 specifically bind to phosphatidylserine (PS) on the surface of apoptotic cells and do not bind to any other phospholipid tested. TIM-4+ peritoneal macrophages, TIM-1+ kidney cells, as well as TIM-4 or TIM-1 transfected cells efficiently phagocytose apoptotic cells and phagocytosis can be blocked by TIM-4 or TIM-1 mAbs. TIM proteins have a unique binding cavity made by an unusual conformation of the CC′ and FG loops of the TIM IgV domain and mutations in this cavity eliminated PS binding and phagocytosis. TIM-4 mAbs that block PS binding and phagocytosis map to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors that recognize PS, critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.
doi:10.1016/j.immuni.2007.11.011
PMCID: PMC2757006  PMID: 18082433
15.  Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology 
Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations.
Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms.
Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions.
doi:10.1186/1479-5876-7-45
PMCID: PMC2724494  PMID: 19534815
16.  MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF 
Journal of Clinical Investigation  2007;117(7):1902-1913.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF–deficient mice develop inflammatory disease. Here we show that GM-CSF is required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8–mediated uptake of apoptotic cells is a key determinant of GM-CSF–triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF–deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-γ promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF–secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF–stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4+ T cell subsets in cancer and autoimmunity.
doi:10.1172/JCI30966
PMCID: PMC1884688  PMID: 17557120

Results 1-16 (16)