Publications by authors named "Tomonori Yaguchi"

55 Publications

AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.

J Exp Med 2021 Sep 29;218(9). Epub 2021 Jul 29.

Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.
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http://dx.doi.org/10.1084/jem.20200962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329870PMC
September 2021

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

Nat Med 2021 Sep 28;27(9):1646-1654. Epub 2021 Jun 28.

Department of Virology, Cochin Hospital, University of Paris, Paris, France.

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2 γδ T, mucosal-associated invariant T and CD56 natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT CD4CD8 double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
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http://dx.doi.org/10.1038/s41591-021-01388-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446316PMC
September 2021

Clinical characteristics of intractable or persistent hiccups and nausea associated with herpes zoster.

Clin Neurol Neurosurg 2021 08 8;207:106751. Epub 2021 Jun 8.

Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan.

Aim: Intractable or persistent hiccups and nausea (IHN) are rarely associated with herpes zoster (HZ-IHN). We aimed to identify the clinical characteristics of HZ-IHN by comparing them with those of neuromyelitis optica spectrum disorder associated with IHN (NMOSD-IHN).

Methods: We collected 8 patients with HZ-IHN and 12 patients with NMOSD-IHN diagnosed between 2002 and 2020 from medical databases. Medical records including clinical information, laboratory data on serum anti-aquaporin 4 (AQP4) antibodies, serological or cerebrospinal fluid findings for the varicella zoster virus, medullary MRI findings, and efficacy of intravenous methylprednisolone pulse (IVMP) therapy were analyzed retrospectively.

Results: The age of onset (69 ± 13 years versus 46 ± 17 years, P = 0.003), percentage of men [7/8 patients (88%) versus 3/12 patients (25%), P = 0.020], serum CRP levels (1.41 ± 1.17 mg/dL versus 0.14 ± 0.33 mg/dL, P = 0.018), and frequency of hemi-cranial nerve involvement [6/8 patients (75%) versus 1/12 patients (8%), P = 0.004] were significantly higher in patients with HZ-IHN than in those with NMOSD-IHN. The hypoglossal and vagus nerves were involved in 5/8 patients (63%) with HZ-IHN. Other clinical parameters, excluding anti-AQP4 antibodies, were similar to those of NMOSD-IHN. MRI revealed ipsilateral hemi-dorsal medullar hyper-intense lesions in 5/8 patients (63%) with HZ-IHN. Acyclovir with IVMP therapy was effective for HZ-IHN.

Conclusion: Clinicians should include HZ-IHN in the differential diagnosis for IHN, and promptly administer acyclovir and IVMP therapy. HZ-IHN is frequently accompanied by lower hemi-cranial nerve palsies and ipsilateral hemi-dorsal medullary hyper-intensity on MRI.

Data Available Statement: The authors confirm that the data supporting the findings of this study are available within the article (Tables 1 and 2), or its supplementary materials (Table S1).
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http://dx.doi.org/10.1016/j.clineuro.2021.106751DOI Listing
August 2021

Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.

Cancer Sci 2021 Aug 30;112(8):3163-3172. Epub 2021 Jun 30.

Institute for Advanced Medical Research, Division of Cellular Signaling, Keio University School of Medicine, Tokyo, Japan.

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
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http://dx.doi.org/10.1111/cas.15009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353905PMC
August 2021

PD-L1 on mast cells suppresses effector CD8 T-cell activation in the skin in murine contact hypersensitivity.

J Allergy Clin Immunol 2021 Aug 10;148(2):563-573.e7. Epub 2021 Feb 10.

Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Singapore Immunology Network (SIgN) and Skin Research Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore. Electronic address:

Background: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8 T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8 T-cell-mediated inflammatory skin diseases remains unclear.

Objective: Our aim was to elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8 T-cell-mediated cutaneous immune responses.

Methods: PD-L1-deficient (Pdl1) mice were used for the murine contact hypersensitivity model. Inflammatory responses such as IFN-γ production from CD8 T cells in the skin was evaluated by flow cytometry.

Results: Compared with wild-type mice, Pdl1 mice exhibited exacerbated ear swelling and increased numbers of IFN-γ CD8 T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γCD8 T cells in the skin of wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-Kit/Kit/J and C57BL/6-KitW/W) mice. The high level of expression of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis.

Conclusion: PD-L1 on MCs negatively regulates CD8 T-cell activation in the skin.
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http://dx.doi.org/10.1016/j.jaci.2020.12.654DOI Listing
August 2021

Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors.

Cancer Sci 2021 Apr 18;112(4):1390-1401. Epub 2021 Mar 18.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8 T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H O , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31 tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H O -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.
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http://dx.doi.org/10.1111/cas.14812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019209PMC
April 2021

Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph B cells but not bone marrow stem/progenitors.

Leuk Lymphoma 2021 03 26;62(3):679-687. Epub 2020 Oct 26.

Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were -negative. Moreover, in some patients was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.
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http://dx.doi.org/10.1080/10428194.2020.1837366DOI Listing
March 2021

Enhanced anti-tumor effects of the PD-1 blockade combined with a highly absorptive form of curcumin targeting STAT3.

Cancer Sci 2020 Dec 20;111(12):4326-4335. Epub 2020 Oct 20.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

PD-1/PD-L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune-resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti-tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen-specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL-6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non-tumor-bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL-6-producing human clear cell ovarian cancer cells. The combination of curcumin and PD-1/PD-L1 Abs demonstrated a synergistic anti-tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen-specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD-1/PD-L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.
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http://dx.doi.org/10.1111/cas.14675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734012PMC
December 2020

The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.

Cancer Res 2020 10 14;80(20):4439-4450. Epub 2020 Sep 14.

Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3993DOI Listing
October 2020

Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy.

Gynecol Oncol 2020 11 20;159(2):329-334. Epub 2020 Aug 20.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Japan.

Objectives: To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3 T cells in 15 fresh samples of cervical cancer.

Methods: In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3 TILs in 15 additional fresh tumor samples were also investigated using flow cytometry.

Results: Infiltration with CD8 TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3, CD4, CD8, CD206, and FOXP3 TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3 TILs, non-Tregs (Fr-III) were found in all samples tested for this.

Conclusions: The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.106DOI Listing
November 2020

Serial evaluation of swallowing function in a long-term survivor of V180I genetic Creutzfeldt-Jakob disease.

Prion 2020 12;14(1):180-184

Department of Neurology, Gifu University Graduate School of Medicine , Gifu, Japan.

Swallowing function in long-term survivors with Creutzfeldt-Jakob disease (CJD) remains unknown. Herein, we demonstrated serial evaluation of swallowing function in a case with V180I genetic CJD (gCJD) using videofluoroscopic examination of swallowing (VF). A 69-year-old woman was admitted to our hospital because of bradykinesia and memory disturbances 4 months after the onset of symptoms. Neurological examination revealed dementia, bradykinesia and frontal signs. Diffusion-weighted MRI revealed bilateral cortical hyperintensity in the frontal, temporal, and parietal cortices, and gene analysis indicated a V180I mutation. Her dysphagia gradually progressed, and she received percutaneous gastrostomy 42 months after the onset. VF was performed at 27, 31, 39, and 79 months after the onset. Although bolus transport from oral cavity to pharynx gradually worsened and initiation of the pharyngeal swallow was gradually delayed, the pharyngeal swallowing function was preserved even at 72 months after onset. MRI revealed no apparent atrophy of brainstem, and single photon emission computed tomography showed preserved regional cerebral blood flow in the brainstem. These findings suggest that the pathophysiology of dysphagia in a long-term survivor of V180I gCJD is that of pseudobulbar palsy, likely owing to preserved brainstem function even in the akinetic mutism state.
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http://dx.doi.org/10.1080/19336896.2020.1787090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518740PMC
December 2020

Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans.

FASEB J 2020 08 3;34(8):10778-10800. Epub 2020 Jul 3.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Chronic graft-vs-host disease (cGVHD) is a multifactorial inflammatory disease that affects patients undergoing hematopoietic stem cell transplantation. Multiple organs, including the lacrimal glands (LGs), are negatively affected by cGVHD and lose function due to the resultant fibrosis. An abnormal immune response is thought to be a major factor in the development of chronic ocular GVHD, which is currently treated primarily with immunosuppressive therapies. However, all the treatments yield unsatisfactory outcomes, and additional treatment strategies are needed. To meet this unmet medical need, we aimed to elucidate an additional pathway of chronic ocular GVHD. Our findings suggest a potential association between chronic ocular GVHD pathogenesis and stress-induced cellular senescence through the senescence-associated secretory phenotype (SASP). Senescent cells produce cytokines and chemokines, such as IL-6 and CXCL9. Indeed, senescent cell accumulation was presumably associated with cGVHD development in LGs, as evidenced by the improvement in LGs after the selective elimination of senescent cells (senolysis) with ABT-263. Results in the sclerodermatous cGVHD mouse model suggest that inhibiting the major components of the SASP, including IL-6 and CXCL9, with senolytics is a potential novel strategy for treating cGVHD-affected LGs. Taken together, our results indicate a potential association between the SASP and cGVHD development in LGs and suggest that targeted senolytic treatment may be a new therapeutic option for this disease.
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http://dx.doi.org/10.1096/fj.201900218RDOI Listing
August 2020

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab.

Elife 2020 03 31;9. Epub 2020 Mar 31.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.
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http://dx.doi.org/10.7554/eLife.49392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108862PMC
March 2020

NUAK2 localization in normal skin and its expression in a variety of skin tumors with YAP.

J Dermatol Sci 2020 Feb 23;97(2):143-151. Epub 2020 Jan 23.

Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Background: NUAK2 is a critical gene that participates in the carcinogenesis of various types of cancers including melanomas. However, the expression patterns of NUAK2 in normal skin and in various types of skin tumors have not been fully elucidated to date.

Objectives: To elucidate the distribution and localization of NUAK2 expression in normal skin, and characterize the expression patterns of NUAK2 and YAP in various types of skin tumors.

Methods: In this study, we characterized the expression of NUAK2 in tissues by developing a novel NUAK2-specific monoclonal antibody and using that to determine NUAK2 expression patterns in normal skin and in 155 cases of various types of skin tumors, including extramammary Paget's disease (EMPD), squamous cell carcinoma (SCC), Bowen's disease (BD), actinic keratosis (AK), basal cell carcinoma (BCC) and angiosarcoma (AS). Further, we analyzed the expression patterns of YAP and p-Akt in those tumors.

Results: Our analyses revealed that NUAK2 is expressed at high frequencies in EMPD, SCC, BD, AK, BCC and AS. The expression of p-Akt was positively correlated with tumor size in EMPD (P = 0.001). Importantly, the expression of NUAK2 was significantly correlated with YAP in SCC (P = 0.012) and in BD (P = 0.009).

Conclusions: Our results suggest that the YAP-NUAK2 axis has critical importance in the tumorigenesis of SCC and BD, and that therapeutic modalities targeting the YAP-NUAK2 axis may be an effective approach against skin tumors including SCC and BD.
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http://dx.doi.org/10.1016/j.jdermsci.2020.01.008DOI Listing
February 2020

Immune-resistant mechanisms in cancer immunotherapy.

Int J Clin Oncol 2020 May 9;25(5):810-817. Epub 2020 Jan 9.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Immune checkpoint inhibitors (ICI) such as PD-1/PD-L1 antibodies (Abs) and CTLA4 Abs and T cell-based adoptive cell therapies are effective for patients with various cancers. However, response rates of ICI monotherapies are still limited due to lack of immunogenic antigens and various immune-resistant mechanisms. The latter includes adaptive immune resistance that is caused by anti-tumor T cells (e.g. PD-L1 induced by IFN-γ from T cells) and primary immune resistance that is caused by cancer cells (e.g. immunosuppressive cytokines produced by cancer cells). Further understanding of the immune-resistant mechanisms, which may be possible through comparative analyses of responders and non-responders to the immunotherapies, will lead to the identification of new diagnostic biomarkers and therapeutic targets for development of effective cancer immuno therapies.
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http://dx.doi.org/10.1007/s10147-019-01611-xDOI Listing
May 2020

Transcription factor homeobox D9 is involved in the malignant phenotype of cervical cancer through direct binding to the human papillomavirus oncogene promoter.

Gynecol Oncol 2019 11 30;155(2):340-348. Epub 2019 Aug 30.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Japan.

Objective: To determine the involvement of homeobox D9 (HOXD9) in the survival, proliferation, and metastasis of cervical cancer cells through regulating the expression of human papillomavirus (HPV) 16 E6/E7 genes using the P97 promoter.

Methods: One hundred cases of cervical cancer (CC), CC cell lines SKG-I, SKG-II, SKG-IIIa, SKG-IIIb, HeLa, and SiHa, and a human tumor xenograft mouse model were used to examine the roles of HOXD9 in CC. Knockdown experiments employed RNA interference of HOXD9. qPCR, functional assays, western blotting, DNA microarray, and luciferase and ChIP assays were applied for assessments.

Results: All CC cell lines expressed HOXD9 mRNA and protein. In uterine CC, HOXD9 gene expression was significantly higher than in normal cervical tissues. A positive correlation of lymphovascular space invasion and lymph node metastasis with high levels of HOXD9 expression was found in patient samples. HOXD9-knockdown cells in the mouse xenograft model only formed small or no tumors. Knockdown of HOXD9 markedly reduced CC cell proliferation, migration and invasion, induced apoptosis, increased P53 protein expression, and suppressed HPV E6/E7 expression by directly binding to the P97 promoter of HPV16 E6/E7 genes. A positive correlation between HOXD9 and HPV16 E6 expression was found in CC patients.

Conclusions: HOXD9 promotes HPV16 E6 and E7 expression by direct binding to the P97 promoter, which enhances proliferation, migration, and metastasis of CCr cells. Our results suggest that HOXD9 could be a prognostic biomarker and potential therapeutic target in CC.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.026DOI Listing
November 2019

Analysis of the Tumor Reactivity of Tumor-Infiltrating Lymphocytes in a Metastatic Melanoma Lesion that Lost Major Histocompatibility Complex Class I Expression after Anti-PD-1 Therapy.

J Invest Dermatol 2019 07 23;139(7):1490-1496. Epub 2019 Jan 23.

Department of Dermatology, University of Yamanashi, Yamanashi, Japan.

Major histocompatibility complex class I loss due to the abnormality of β2-microglobulin gene is one of the mechanisms underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes in tumor lesions that lost major histocompatibility complex class I expression has not been well evaluated. We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again. We resected both lesions and examined the tumor cells and tumor-infiltrating lymphocytes. The shrinking lesion consisted of necrotic tissue and macrophages, and the enlarged lesion consisted of both necrotic tissue and viable tumor cells. The tumor cells completely lost major histocompatibility complex class I expression, but it was restored upon retroviral transduction of the normal β2-microglobulin gene. When we checked the tumor-specific reactivity of tumor-infiltrating lymphocytes derived from the relapsing lesion, we found that these tumor-infiltrating lymphocytes failed to recognize the native tumor cells derived from the lesion, but strongly recognized the major histocompatibility complex class-I-recovered cells by β2-microglobulin transduction. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.
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http://dx.doi.org/10.1016/j.jid.2019.01.007DOI Listing
July 2019

A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.

Nature 2019 01 23;565(7741):600-605. Epub 2019 Jan 23.

Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103 dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.
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http://dx.doi.org/10.1038/s41586-019-0878-zDOI Listing
January 2019

Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms.

Lung Cancer 2018 05 2;119:25-35. Epub 2018 Mar 2.

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors.

Materials And Methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs.

Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β, Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis.

Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.
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http://dx.doi.org/10.1016/j.lungcan.2018.02.015DOI Listing
May 2018

Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses.

Cell Mol Immunol 2018 11 20;15(11):953-962. Epub 2017 Nov 20.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.

Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses. However, when human peripheral blood mononuclear cells (PBMCs) are transferred into NOG (NOD/Shi-scid, IL-2rg) mice, severe graft versus host disease (GVHD) hinders long term detailed analysis. Administration of human PBMCs into newly developed murine MHC class I- and class II-deficient NOG (NOG-dKO; NOG- Iab, B2m-double-knockout) mice showed sufficient engraftment of human immune cells with little sign of GVHD. Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab, indicating induction of antigen-specific B cells in the NOG-dKO mice. Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells, indicating the induction of antigen-specific T cells in the NOG-dKO mice. Adoptive cell therapies (ACTs) using melanoma antigen recognized by T cells (MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells. ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice, in which changes in human cancer phenotypes by immune intervention, such as increased CD271 expression, could be evaluated. Therefore, NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.
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http://dx.doi.org/10.1038/cmi.2017.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207709PMC
November 2018

Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment.

Cancer Sci 2018 Jan 9;109(1):54-64. Epub 2017 Nov 9.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune-checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin-angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAF). Last, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8 T cell-dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD-1/PD-L1 immune-checkpoint blockade therapy.
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http://dx.doi.org/10.1111/cas.13423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765296PMC
January 2018

Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma.

Eur J Cancer 2017 11 23;86:15-27. Epub 2017 Sep 23.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan. Electronic address:

We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8 T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8 T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8 T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8 T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8 T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8 FOXP3 T cells and immunodysfunctional CD8 GATA3 T cells were increased in adenocarcinoma of non-smokers. CD4 FOXP3 regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163 M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.
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http://dx.doi.org/10.1016/j.ejca.2017.08.026DOI Listing
November 2017

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies.

Nihon Rinsho Meneki Gakkai Kaishi 2017 ;40(1):68-77

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine.

  Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.
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http://dx.doi.org/10.2177/jsci.40.68DOI Listing
September 2017

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer.

Nihon Rinsho Meneki Gakkai Kaishi 2017 ;40(1):54-59

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine.

  Efficacy of immune checkpoint inhibitors such as PD-1 antibody for colorectal cancer remains to be proved except in microsatellite-instability-high (MSI-H) cases. While the objective response rate of MSI-H cases was 40%, that of microsatellite-stable (MSS) cases was 0%, showing that response rate to immune checkpoint inhibitors varies even among the microsatellite status. Some possible mechanisms that confer each patient variation in the response to immunotherapy should be considered. We focused on the combination of inter-patient heterogeneity and intra-tumor heterogeneity as a determining factor of immune reaction. An example of intra-tumor heterogeneity is the low expression of tumor antigen by CD271 cells in melanoma. It is not surprising that similar mechanism exists in CRC. Other related intra-tumor heterogeneity includes EMT and autophagy, both molecular mechanisms that are thought to promote immune-evading phenotype. Besides the microsatellite status, inter-patient heterogeneity in response to tumor immunity includes hypermutator phenotype, which is driven by POLE mutation, intrinsic cytokine production, and microbiota in the gut.
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http://dx.doi.org/10.2177/jsci.40.54DOI Listing
September 2017

CHD7 promotes proliferation of neural stem cells mediated by MIF.

Mol Brain 2016 12 13;9(1):96. Epub 2016 Dec 13.

Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas.
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http://dx.doi.org/10.1186/s13041-016-0275-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154087PMC
December 2016

The first clinical experience with a novel directional coronary atherectomy catheter: Preliminary Japanese multicenter experience.

Catheter Cardiovasc Interv 2017 Apr 12;89(5):880-887. Epub 2016 Jul 12.

Department of Cardiovascular Medicine, Toyohashi Heart Center, Aichi, Japan.

Aims: Despite development of drug eluting stents (DES), percutaneous coronary intervention (PCI) for bifurcation lesions using DES alone remains challenging. The aim of this study was to report on the initial clinical experience with a novel directional coronary atherectomy (DCA) catheter.

Methods And Results: Patients with de novo bifurcation lesions were entered into a prospective registry and a novel DCA catheter was used. Device, procedural success and in-hospital outcomes were evaluated. A total of 14 patients with bifurcation lesions were enrolled. DCA was performed successfully in all cases without any major procedure-related events (device success rate: 100%, procedural success rate: 100%). Four patients (29%) were treated without stent implantation and simple stenting was achieved in the other 10 patients. No in-hospital major adverse cardiac event was observed.

Conclusions: PCI with a novel DCA catheter for bifurcation lesions may be safe and effective. The clinical significance of these findings needs to be determined in future studies. This study was performed to evaluate the safety and efficacy of a novel directional coronary atherectomy catheter for bifurcation lesions. Both the device and procedural success rates were 100%. Complex stenting could be avoided in all cases. No inhospital major adverse cardiac event was observed. The novel directional coronary atherectomy catheter may be safe and effective for bifurcation lesions, even in this drug eluting stent era. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ccd.26627DOI Listing
April 2017

Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation.

Int Immunol 2016 08 8;28(8):393-9. Epub 2016 Jul 8.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Although recent cancer immunotherapy strategies, including immune-checkpoint blockade (i.e. blocking PD-1, PD-L1 or CTLA-4), have shown durable clinical effects in some (but not all) patients with various advanced cancers, further understanding of human immunopathology, particularly in tumor microenvironments, is essential to improve this type of therapy. The major hurdle for immunotherapy is the immunosuppression that is found in cancer patients. There are two types of immunosuppression: one is induced by gene alterations in cancer; the other is local adaptive immunosuppression, triggered by tumor-specific T cells in tumors. The former is caused by multiple mechanisms via various immunosuppressive molecules and via cells triggered by gene alterations, including activated oncogenes, in cancer cells. The various immunosuppressive mechanisms involve signaling cascades that vary among cancer types, subsets within cancer types and individual cancers. Therefore, personalized immune-interventions are necessary to appropriately target oncogene-induced signaling that modulates anti-cancer immune responses, on the basis of genetic and immunological analysis of each patient. Further understanding of human cancer immunopathology may lead to real improvement of current cancer immunotherapies.
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http://dx.doi.org/10.1093/intimm/dxw030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986236PMC
August 2016

MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53.

Cancer Res 2016 05 15;76(9):2813-23. Epub 2016 Mar 15.

Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan.

Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere-forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. Cancer Res; 76(9); 2813-23. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1011DOI Listing
May 2016

MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model.

Elife 2016 Jan 26;5:e09394. Epub 2016 Jan 26.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Fibrosis of organs is observed in systemic autoimmune disease. Using a scleroderma mouse, we show that transplantation of MHC compatible, minor antigen mismatched bone marrow stromal/stem cells (BMSCs) play a role in the pathogenesis of fibrosis. Removal of donor BMSCs rescued mice from disease. Freshly isolated PDGFRα(+) Sca-1(+) BMSCs expressed MHC class II following transplantation and activated host T cells. A decrease in FOXP3(+) CD25(+) Treg population was observed. T cells proliferated and secreted IL-6 when stimulated with mismatched BMSCs in vitro. Donor T cells were not involved in fibrosis because transplanting T cell-deficient RAG2 knock out mice bone marrow still caused disease. Once initially triggered by mismatched BMSCs, the autoimmune phenotype was not donor BMSC dependent as the phenotype was observed after effector T cells were adoptively transferred into naïve syngeneic mice. Our data suggest that minor antigen mismatched BMSCs trigger systemic fibrosis in this autoimmune scleroderma model.
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http://dx.doi.org/10.7554/eLife.09394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739756PMC
January 2016
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