紅林　泰 (クレバヤシ　ユタカ)

Kurebayashi, Yutaka

写真a

所属（所属キャンパス）

医学部 病理学教室 （信濃町）

職名

専任講師（有期）
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経歴 【 表示 ／ 非表示 】

  • 2022年04月
    -
    継続中

    慶應義塾大学医学部, 病理学教室, 専任講師（学部内）

  • 2017年04月
    -
    2022年03月

    慶應義塾大学医学部, 病理学教室, 助教

  • 2018年09月
    -
    2020年09月

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

  • 2018年04月
    -
    2018年09月

    国立病院機構埼玉病院, 臨床検査科　病理, 医師

  • 2016年04月
    -
    2016年09月

    川崎市立川崎病院, 検査科 病理, 医員

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学歴 【 表示 ／ 非表示 】

  • 2005年04月
    -
    2011年03月

    慶應義塾大学, 医学部, 医学科

    大学, 卒業

  • 2013年04月
    -
    2017年03月

    慶應義塾大学, 医学研究科, 病理学専攻

    大学院, 修了, 博士

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学位 【 表示 ／ 非表示 】

  • 博士（医学）/Ph.D., 慶應義塾大学, 課程, 2017年03月

  • 学士（医学）/M.D., 慶應義塾大学, 2011年03月

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免許・資格 【 表示 ／ 非表示 】

  • 医師免許, 2011年03月

  • 死体解剖資格, 2015年07月

  • 日本病理学会認定病理専門医, 2017年08月

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 人体病理学

  • ライフサイエンス / 実験病理学

  • ライフサイエンス / 免疫学

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論文 【 表示 ／ 非表示 】

  • 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年04月

    ISSN  1386-6346

    　概要を見る

    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年12月

    ISSN  0027-8424

    　概要を見る

    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年12月

    　概要を見る

    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年10月

    ISSN  0270-9139

    　概要を見る

    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年06月

    ISSN  0008-5472

    　概要を見る

    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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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 全ての病期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成立機序の解明

    2021年04月
    -
    2025年03月

    慶應義塾大学, 紅林 泰, 若手研究, 未設定

    　研究概要を見る

    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。

  • 肝細胞癌における免疫微小環境の網羅的解析

    2017年08月
    -
    2019年03月

    日本学術振興会, 研究活動スタート支援, 紅林　泰, 研究活動スタート支援, 補助金,  研究代表者

    　研究概要を見る

    肝細胞癌の免疫微小環境を検討するため、肝細胞癌切除検体の標本上において様々な種類の免疫細胞を染め分け（多重免疫染色）、顕微鏡を用いて各免疫細胞の数と分布を詳細に検討した。統計学的に解析した結果、肝細胞癌における免疫微小環境は３つのパターンに分類されることがわかった。このうちImmune-highパターンとした一群はT細胞とB細胞・形質細胞の共浸潤に特徴付けられ、このような免疫微小環境を呈する肝細胞癌は術後の再発率が有意に低かった。また、肝細胞癌が多段階発癌の良いモデルであることを用いて、肝細胞癌の多段階発癌の過程で免疫微小環境も段階的に変化することを示した。
    癌に含まれる多様な免疫細胞がどのような組み合わせて浸潤して免疫微小環境を形成しているのかに関しては不明な点が多かった。本研究の学術的意義は、肝細胞癌における免疫微小環境の全体像を組織病理学的に最も直接的な形で示すことで、その疑問に答えた点にある。社会的意義としては、免疫微小環境の分類が、従来の病理学的・分子生物学的分類に加えて肝細胞癌の予後予測因子として重要であり、臨床病理学的にも応用が可能であることを示した点が挙げられる。

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受賞 【 表示 ／ 非表示 】

  • 日本病理学会100周年記念病理学研究新人賞

    2016年05月, 日本病理学会

    受賞区分： 国内学会・会議・シンポジウム等の賞

  • 日本免疫学会 Young Investigator's Award

    2010年08月, 日本免疫学会

    受賞区分： 国内学会・会議・シンポジウム等の賞

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担当授業科目 【 表示 ／ 非表示 】

  • 病理学総論

    2024年度

  • 病理学各論

    2024年度

  • 病理学総論

    2023年度

  • 病理学各論

    2023年度

  • 病理学総論

    2022年度

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所属学協会 【 表示 ／ 非表示 】

  • 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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