Kurebayashi, Yutaka

写真a

Affiliation

School of Medicine, Department of Pathology (Shinanomachi)

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)

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

display all >>

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

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

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

 

Research Areas 【 Display / hide

  • Life Science / Human pathology

  • Life Science / Experimental pathology

  • Life Science / Immunology

 

Papers 【 Display / hide

  • Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy.

    Kurebayashi Y, Tsujikawa H, Sugimoto K, Yunaiyama D, Araki Y, Saito K, Takahashi H, Kakegawa T, Wada T, Tomita Y, Abe M, Yoshimasu Y, Takeuchi H, Hirata T, Sakamaki K, Kakimi K, Nagao T, Itoi T, Sakamoto M

    Hepatology research : the official journal of the Japan Society of Hepatology (Hepatology Research)  53 ( 10 ) 1008 - 1020 2023.10

    ISSN  1386-6346

     View Summary

    Aim: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy. Methods: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0–1500 s/mm2), and other clinicopathologic factors were analyzed. Results: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS. Conclusions: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

  • IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis.

    Fujimori S, Chu PS, Teratani T, Harada Y, Suzuki T, Amiya T, Taniki N, Kasuga R, Mikami Y, Koda Y, Ichikawa M, Tabuchi T, Morikawa R, Yamataka K, Noguchi F, Tsujikawa H, Kurebayashi Y, Sakamoto M, Kanai T, Nakamoto N

    JHEP reports : innovation in hepatology (JHEP Reports)  5 ( 7 ) 100757 2023.07

     View Summary

    Background & Aims: B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods: Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results: B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions: This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications: IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.

  • 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.

  • Two Distinct Characteristics of Immune Microenvironment in Human Hepatocellular Carcinoma with Wnt/β-Catenin Mutations

    Aoki T., Nishida N., Kurebayashi Y., Sakai K., Morita M., Chishina H., Takita M., Hagiwara S., Ida H., Ueshima K., Minami Y., Tsurusaki M., Nakai T., Sakamoto M., Nishio K., Kudo M.

    Liver Cancer (Liver Cancer)   2023

    ISSN  22351795

     View Summary

    Introduction: Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. Methods: This study includes 152 resected HCCs; mutations in the catenin beta-1, adenomatous polyposis coli, or AXIN1, or AXIN2 genes were defined as Wnt/βcatenin mutations. With hierarchical cluster analyses, TME was classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME. Results: Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells, and myeloid-derived suppressor cell activation and recognized as low enhancement nodule Tomoko Aoki and Naoshi Nishida contributed equally to this manuscript. on Gd-EOB-DTPA-enhanced MRI. Conclusion: Heterogeneity of tumor traits and TME was observed in HCC with Wnt/βcatenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1, both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway.

  • 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.

display all >>

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, Grants-in-Aid for Scientific Research, 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

     View Summary

    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.

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.

 

Courses Taught 【 Display / hide

  • GENERAL PATHOLOGY

    2024

  • DISEASES OF ORGAN SYSTEMS

    2024

  • GENERAL PATHOLOGY

    2023

  • DISEASES OF ORGAN SYSTEMS

    2023

  • GENERAL PATHOLOGY

    2022

display all >>

 

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