Kurebayashi, Yutaka

写真a

Affiliation

School of Medicine, Department of Pathology （Shinanomachi）

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)
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Career 【 Display / hide 】

  • 2022.04
    -
    Present

    Keio University School of Medicine, Department of Pathology, Assistant Professor

  • 2017.04
    -
    2022.03

    Keio University School of Medicine, Department of Pathology, Instructor/Research Associate

  • 2018.09
    -
    2020.09

    National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA, Molecular Imaging Branch, Postdoctoral Fellow

  • 2018.04
    -
    2018.09

    National Hospital Organization Saitama Hospital, Department of Pathology, Pathologist

  • 2016.04
    -
    2016.09

    Kawasaki City Kawasaki Hospital, Department of Pathology, Pathologist

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Academic Background 【 Display / hide 】

  • 2005.04
    -
    2011.03

    Keio University, School of Medicine, 医学科

    University, Graduated

  • 2013.04
    -
    2017.03

    Keio University, School of Medicine (Ph.D. course), 病理学専攻

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（医学）/Ph.D., Keio University, Coursework, 2017.03

  • 学士（医学）/M.D., Keio University, 2011.03

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Licenses and Qualifications 【 Display / hide 】

  • 医師免許, 2011.03

  • 死体解剖資格, 2015.07

  • 日本病理学会認定病理専門医, 2017.08

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Research Areas 【 Display / hide 】

  • Life Science / Human pathology

  • Life Science / Experimental pathology

  • Life Science / Immunology

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Papers 【 Display / hide 】

  • Immunovascular microenvironment in relation to prognostic heterogeneity of WNT/β-catenin-activated hepatocellular carcinoma.

    Matsuda K, Kurebayashi Y, Masugi Y, Yamazaki K, Ueno A, Tsujikawa H, Ojima H, Kitago M, Itano O, Shinoda M, Abe Y, Sakamoto M

    Hepatology research : the official journal of the Japan Society of Hepatology （Hepatology Research)  53 （ 4 ） 344 - 356 2023.04

    ISSN  1386-6346

    　View Summary

    Aim: WNT/β-catenin-activated hepatocellular carcinoma (W/B subclass HCC) is considered a molecularly homogeneous entity and has been linked to resistance to immunotherapy. However, recent studies have indicated possible heterogeneity in the immunovascular microenvironment in this subclass. We set out to test the hypothesis that specific immunovascular features might stratify W/B subclass HCCs into tumors having distinct aggressive natures. Methods: In this study, we analyzed 352 resected HCCs including 78 immunohistochemically defined W/B subclass HCCs. The density of tumor-infiltrating CD3+ T cells and the area ratio of vessels encapsulating tumor clusters (VETC) were calculated on tissue specimens. The gene expressions of angiogenic factors were measured by quantitative reverse transcription–polymerase chain reaction. Disease-free survival (DFS) was assessed using multivariable Cox regression analyses. Results: The T-cell density of W/B subclass HCCs was regionally heterogenous within tumor tissues, and focally reduced T-cell density was observed in areas with VETC. VETC-positivity (defined as VETC area ratio greater than 1%) was inversely associated with T-cell infiltration in both W/B subclass and non-W/B subclass HCCs. Fibroblast growth factor 2 (FGF2) gene expression was higher in W/B subclass than in non-W/B subclass HCCs. The VETC-positivity and low T-cell density correlated with increased expression of FGF2 in W/B subclass HCCs. Additionally, VETC-positive HCCs showed significantly shorter DFS in W/B subclass HCCs. Conclusions: In conclusion, the immune and vascular microenvironments are interrelated and are also correlated with clinicopathological heterogeneity in W/B subclass HCC. These results could inform clinical practice and translational research on the development of therapeutic stratification of HCCs.

  • Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus.

    Iriki H, Takahashi H, Wada N, Nomura H, Mukai M, Kamata A, Ito H, Yamagami J, Matsui T, Kurebayashi Y, Mise-Omata S, Nishimasu H, Nureki O, Yoshimura A, Hori S, Amagai M

    Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America)  118 （ 49 ）  2021.12

    ISSN  0027-8424

    　View Summary

    Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg32/2 mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

  • The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

    El Bairi K., Haynes H.R., Blackley E., Fineberg S., Shear J., Turner S., de Freitas J.R., Sur D., Amendola L.C., Gharib M., Kallala A., Arun I., Azmoudeh-Ardalan F., Fujimoto L., Sua L.F., Liu S.W., Lien H.C., Kirtani P., Balancin M., El Attar H., Guleria P., Yang W., Shash E., Chen I.C., Bautista V., Do Prado Moura J.F., Rapoport B.L., Castaneda C., Spengler E., Acosta-Haab G., Frahm I., Sanchez J., Castillo M., Bouchmaa N., Md Zin R.R., Shui R., Onyuma T., Yang W., Husain Z., Willard-Gallo K., Coosemans A., Perez E.A., Provenzano E., Ericsson P.G., Richardet E., Mehrotra R., Sarancone S., Ehinger A., Rimm D.L., Bartlett J.M.S., Viale G., Denkert C., Hida A.I., Sotiriou C., Loibl S., Hewitt S.M., Badve S., Symmans W.F., Kim R.S., Pruneri G., Goel S., Francis P.A., Inurrigarro G., Yamaguchi R., Garcia-Rivello H., Horlings H., Afqir S., Salgado R., Adams S., Kok M., Dieci M.V., Michiels S., Demaria S., Loi S., Haynes H.R., Fineberg S., Shear J., Turner S., de Freitas J.R., Sur D., Amendola L.C., Gharib M., Arun I., Fujimoto L., Liu S.W., Lien H.C., Yang W., Chen I.C., Bautista V.

    npj Breast Cancer （npj Breast Cancer)  7 （ 1 ）  2021.12

    　View Summary

    The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

  • Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments.

    Kurebayashi Y, Matsuda K, Ueno A, Tsujikawa H, Yamazaki K, Masugi Y, Kwa WT, Effendi K, Hasegawa Y, Yagi H, Abe Y, Kitago M, Ojima H, Sakamoto M

    Hepatology (Baltimore, Md.) （Hepatology)  75 （ 5 ） 1139 - 1153 2021.10

    ISSN  0270-9139

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    Background and Aims: Immune cells and tumor vessels constitute important elements in tumor tissue; however, their detailed relationship in human tumors, including HCC, is still largely unknown. Consequently, we expanded our previous study on the immune microenvironment of HCC and analyzed the relationship among the immune microenvironment, inflammatory/angiostatic factor expression, angiogenic factor expression, and tumor vessel findings, including vessels encapsulating tumor clusters (VETC) and macrotrabecular-massive (MTM) patterns. Approach and Results: We classified HCC into four distinct immunovascular subtypes (immune-high/angiostatic [IH/AS], immune-mid/angio-mid [IM/AM], immune-low/angiogenic [IL/AG], and immune-low/angio-low [IL/AL]). IH/AS, IM/AM, and IL/AG subtypes were associated with decreasing lymphocytic infiltration and increasing angiogenic factor expression and VETC/MTM positivity, reflecting their reciprocal interaction in the tumor microenvironment of HCC. IL/AG subtype was further characterized by CTNNB1 mutation and activation of Wnt/β-catenin pathway. IL/AL subtype was not associated with increased lymphocyte infiltration or angiogenic factor expression. Prognostically, IH/AS subtype and VETC/MTM positivity were independently significant in two independent cohorts. Increased angiogenic factor expression was not necessarily associated with VETC/MTM positivity and poor prognosis, especially when inflammatory/angiostatic milieu coexisted around tumor vessels. These results may provide insights on the therapeutic effects of immunotherapy, antiangiogenic therapies, and their combinations. The potential of evaluating the immunovascular microenvironment in predicting the clinical effect of these therapies in nonresectable HCC needs to be analyzed in the future study. Conclusions: HCC can be classified into four distinct immunovascular subtypes (IH/AS, IM/AM, IL/AG, and IL/AL) that reflect the reciprocal interaction between the antitumor immune microenvironment and tumor angiogenesis. In addition to its clinicopathological significance, immunovascular classification may also provide pathological insights on the therapeutic effect of immunotherapy, antiangiogenic therapy, and their combination.

  • Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.

    Kurebayashi Y, Olkowski CP, Lane KC, Vasalatiy OV, Xu BC, Okada R, Furusawa A, Choyke PL, Kobayashi H, Sato N

    Cancer research （Cancer Research)  81 （ 11 ） 3092 - 3104 2021.06

    ISSN  0008-5472

    　View Summary

    Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab0)2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNg expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNg produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNg receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNg, providing insight into the mechanism of Treg-targeting therapies.

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Histopathological classification of the immune microenvironment of hepatocellular carcinoma including all clinical stages

    2021.04
    -
    2025.03

    Keio University, Grant-in-Aid for Early-Career Scientists, No Setting

    　View Summary

    がんに対する免疫療法の進展を受けて、肝細胞癌の免疫微小環境の分類の確立ならびに病理診断への応用が期待されている。一方で、これまでの研究は手術により切除可能な比較的早期の肝細胞癌を主な対象としており、免疫療法の対象となる切除不能進行肝細胞癌の免疫微小環境については未だに不明である。本研究では、研究代表者がこれまでに検討した外科切除可能な肝細胞癌症例に加えて進行肝細胞癌の病理解剖例を改めて詳細に解析することで、①全ての病期（前癌病変、早期肝細胞癌から切除不能進行肝細胞癌まで）における肝細胞癌の免疫微小環境の病理学的分類の確立と、②各免疫微小環境の成立機序の一端の解明を目指す。

  • Comprehensive analysis of immune microenvironment in hepatocellular carcinoma (HCC)

    2017.08
    -
    2019.03

    Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Research Activity start-up, Yutaka Kurebayashi, Grant-in-Aid for Research Activity Start-up, Principal investigator

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    To analyze the patterns of anti-tumor immunity against hepatocellular carcinoma (HCC), we performed multi-color immunohistochemistry to histopathologically evaluate various immune cells and analyzed the number and distribution of each type of immune cells using microscopy. Consequently, we revealed that the patterns of anti-tumor immunity against HCC can be classified into 3 patterns, among which "Immune-high pattern" was characterized by the co-infiltration of T cells and B/plasma cells and significantly associated with better prognosis after surgical resection of HCC. We also revealed how the pattern of anti-tumor immunity changes during the course of multi-step carcinogenesis of HCC.

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Awards 【 Display / hide 】

  • 日本病理学会100周年記念病理学研究新人賞

    2016.05, 日本病理学会

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 日本免疫学会 Young Investigator's Award

    2010.08, 日本免疫学会

    Type of Award： Award from Japanese society, conference, symposium, etc.

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Courses Taught 【 Display / hide 】

  • GENERAL PATHOLOGY

    2023

  • DISEASES OF ORGAN SYSTEMS

    2023

  • GENERAL PATHOLOGY

    2022

  • DISEASES OF ORGAN SYSTEMS

    2022

  • GENERAL PATHOLOGY

    2021

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Memberships in Academic Societies 【 Display / hide 】

  • 日本病理学会

    　

  • 日本免疫学会

    　

  • 日本臨床細胞学会

    　

  • American Association for Cancer Research

    　
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