2024/05/20 更新

写真a

ナガサキ ジョウジ
長﨑 譲慈
Joji Nagasaki
所属
医歯薬学域 助教
職名
助教

学位

  • 博士(医学) ( 2021年   大阪市立大学 )

研究キーワード

  • 血液内科学

  • 腫瘍免疫学

研究分野

  • ライフサイエンス / 免疫学

  • ライフサイエンス / 血液、腫瘍内科学

  • ライフサイエンス / 腫瘍生物学

学歴

  • 大阪市立大学    

    2016年4月 - 2021年9月

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  • 和歌山県立医科大学    

    2004年4月 - 2010年3月

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経歴

  • 国立大学法人岡山大学学術研究院医歯薬学域 腫瘍微小環境学分野

    2022年4月 - 現在

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  • 大阪市立大学医学部附属病院   血液内科・造血幹細胞移植科

    2021年10月 - 2022年3月

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  • 生長会府中病院   血液疾患センター

    2013年10月 - 2016年3月

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  • 大阪市立大学附属病院   血液内科・造血幹細胞移植科

    2012年4月 - 2013年9月

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所属学協会

 

論文

  • Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment. 国際誌

    Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Masahito Kawazu, Hiromichi Dansako, Yutaka Suzuki, Hiroyoshi Nishikawa, Takashi Inozume, Joji Nagasaki, Yosuke Togashi

    Cell reports   43 ( 2 )   113797 - 113797   2024年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

    DOI: 10.1016/j.celrep.2024.113797

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  • PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes. 国際誌

    Joji Nagasaki, Takashi Inozume, Nicolas Sax, Ryo Ariyasu, Masakazu Ishikawa, Kazuo Yamashita, Masahito Kawazu, Toshihide Ueno, Takuma Irie, Etsuko Tanji, Takao Morinaga, Akiko Honobe, Takehiro Ohnuma, Mitsuru Yoshino, Takekazu Iwata, Katsushige Kawase, Keita Sasaki, Toyoyuki Hanazawa, Vitaly Kochin, Tatsuyoshi Kawamura, Hiroyuki Matsue, Masayuki Hino, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Yosuke Togashi

    Cell reports   38 ( 5 )   110331 - 110331   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.

    DOI: 10.1016/j.celrep.2022.110331

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  • The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. 国際誌

    Joji Nagasaki, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Masato Sugano, Yuuki Ohara, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa

    Blood advances   4 ( 17 )   4069 - 4082   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I-MHC-II+ tumors but not on MHC-I-MHC-II- tumors, in a cytotoxic CD4+ T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II-expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II-expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

    DOI: 10.1182/bloodadvances.2020002098

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  • Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome. 国際誌

    Joji Nagasaki, Yasutaka Aoyama, Masayuki Hino, Kentaro Ido, Hiroyoshi Ichihara, Masahiro Manabe, Tadanobu Ohta, Atsuko Mugitani

    Acta haematologica   137 ( 1 )   32 - 39   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. METHODS: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. RESULTS: WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). CONCLUSIONS: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

    DOI: 10.1159/000452732

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  • T cells with high BCL-2 expression induced by venetoclax impact anti-leukemic immunity "graft-versus-leukemia effects". 国際誌

    Joji Nagasaki, Mitsutaka Nishimoto, Hideo Koh, Hiroshi Okamura, Mika Nakamae, Kazuki Sakatoku, Kentaro Ido, Masatomo Kuno, Yosuke Makuuchi, Teruhito Takakuwa, Yasuhiro Nakashima, Masayuki Hino, Hirohisa Nakamae

    Blood cancer journal   14 ( 1 )   79 - 79   2024年5月

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  • CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling. 国際誌

    Yuto Naoi, Takao Morinaga, Joji Nagasaki, Ryo Ariyasu, Youki Ueda, Kazuo Yamashita, Wenhao Zhou, Shusuke Kawashima, Katsushige Kawase, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Masahito Kawazu, Yutaka Suzuki, Hiroyoshi Nishikawa, Toyoyuki Hanazawa, Mizuo Ando, Takashi Inozume, Yosuke Togashi

    Cancer research   2024年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.

    DOI: 10.1158/0008-5472.CAN-23-0453

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  • Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors. 国際誌

    Hideki Ikeda, Joji Nagasaki, Daiki Shimizu, Yuki Katsuya, Hidehito Horinouchi, Yukio Hosomi, Etsuko Tanji, Takekazu Iwata, Makiko Itami, Masahito Kawazu, Yuichiro Ohe, Takuji Suzuki, Yosuke Togashi

    JTO clinical and research reports   4 ( 10 )   100573 - 100573   2023年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs). METHODS: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II-expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo. RESULTS: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti-programmed cell death protein 1 monoclonal antibody. CONCLUSIONS: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.

    DOI: 10.1016/j.jtocrr.2023.100573

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  • CTLA-4の単純な阻害はTreg細胞のCTLA-4以外の免疫抑制機構の活性化を引き起こす(Anti-tumor effects of CTLA-4 blockade are distrubed by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 丸山 雄樹, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    日本癌学会総会記事   82回   1380 - 1380   2023年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies. 国際誌

    Naoya Kemmotsu, Kiichiro Ninomiya, Kei Kunimasa, Takamasa Ishino, Joji Nagasaki, Yoshihiro Otani, Hiroyuki Michiue, Eiki Ichihara, Kadoaki Ohashi, Takako Inoue, Motohiro Tamiya, Kazuko Sakai, Youki Ueda, Hiromichi Dansako, Kazuto Nishio, Katsuyuki Kiura, Isao Date, Yosuke Togashi

    International journal of cancer   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.

    DOI: 10.1002/ijc.34700

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  • Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models. 国際誌

    Naoya Kemmotsu, Li Zhu, Joji Nagasaki, Yoshihiro Otani, Youki Ueda, Hiromichi Dansako, Yue Fang, Isao Date, Yosuke Togashi

    Cancer science   114 ( 10 )   3848 - 3856   2023年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hydrogen peroxide (H2 O2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H2 O2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H2 O2 on antitumor immunity remain unclear. To investigate the effects of H2 O2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H2 O2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H2 O2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H2 O2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H2 O2 /RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8+ (cluster of differentiation 8) T cells and the frequency of IFN-γ+ (interferon gamma) CD8+ T cells were higher in the noninjected/nonirradiated tumors in the H2 O2 /RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H2 O2 /RT group. Intratumoral injection of H2 O2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H2 O2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.

    DOI: 10.1111/cas.15911

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  • High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects. 国際誌

    Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Etsuko Tanji, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi

    Cancer immunology research   11 ( 7 )   OF1-OF14 - 908   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB-targeted therapies to overcome such resistance.

    DOI: 10.1158/2326-6066.CIR-22-0815

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  • Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. 国際誌

    Tomofumi Watanabe, Takamasa Ishino, Youki Ueda, Joji Nagasaki, Takuya Sadahira, Hiromichi Dansako, Motoo Araki, Yosuke Togashi

    Cancer science   114 ( 5 )   1859 - 1870   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that only CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.

    DOI: 10.1111/cas.15756

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  • Mechanisms of resistance to immune checkpoint inhibitors. 国際誌

    Joji Nagasaki, Takamasa Ishino, Yosuke Togashi

    Cancer science   113 ( 10 )   3303 - 3312   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.

    DOI: 10.1111/cas.15497

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  • Mixed response to cancer immunotherapy is driven by intratumor heterogeneity and differential inter-lesion immune infiltration

    Takao Morinaga, Takashi Inozume, Masahito Kawazu, Youki Ueda, Nicolas Sax, Kazuo Yamashita, Shusuke Kawashima, Joji Nagasaki, Toshihide Ueno, Jason Lin, Yuuki Ohara, Takeshi Kuwata, Hiroki Yukami, Akihito Kawazoe, Kohei Shitara, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Ayako Morita, Eiki Ichihara, Katsuyuki Kiura, Tomohiro Enokida, Makoto Tahara, Yoshinori Hasegawa, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Yosuke Togashi

    Cancer Research Communications   2 ( 7 )   739 - 753   2022年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:American Association for Cancer Research (AACR)  

    Abstract

    Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TILs) demonstrated a significant difference in tumor clonality and TILs’ characteristics, especially exhausted T cell clonotypes, although a close relationship between the tumor cell and T cell clones were observed as a response of an overlapped exhausted T cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to PD-1 blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.

    DOI: 10.1158/2767-9764.crc-22-0050

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  • A variety of 'exhausted' T cells in the tumor microenvironment. 国際誌

    Joji Nagasaki, Yosuke Togashi

    International immunology   34 ( 11 )   563 - 570   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In T cell biology, 'exhaustion' was initially described as a hyporesponsive state in CD8 + T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term 'exhaustion' is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The upregulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8 + T cells, CD4 + T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Upregulation of the same inhibitory receptors that are associated with CD8 + T-cell exhaustion has also been identified in CD4 + T cells in chronic infections and cancers, suggesting a similar CD4 + T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4 + T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust antitumor immune response.

    DOI: 10.1093/intimm/dxac013

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  • Immunomodulatory and direct activities of ropeginterferon alfa-2b on cancer cells in mouse models of leukemia. 国際誌

    Kazuki Sakatoku, Yasuhiro Nakashima, Joji Nagasaki, Mitsutaka Nishimoto, Asao Hirose, Mika Nakamae, Hideo Koh, Masayuki Hino, Hirohisa Nakamae

    Cancer science   113 ( 7 )   2246 - 2257   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. Ropeginterferon alfa-2b therapy significantly prolonged the survival of mice bearing leukemia cells and led to long-term remission in some mice. Alternatively, conventional interferon-alpha treatment slightly extended the survival and all mice died. When ropeginterferon alfa-2b was administered to interferon-alpha receptor 1-knockout mice after the development of leukemia to verify the direct effect on the tumor, the survival of these mice was slightly prolonged; nevertheless, all of them died. In vivo CD4+ or CD8+ T-cell depletion resulted in a significant loss of therapeutic efficacy in mice. These results indicate that the host adoptive immunostimulatory effect of ropeginterferon alfa-2b is the dominant mechanism through which tumor cells are suppressed. Moreover, mice in long-term remission did not develop leukemia, even after tumor rechallenge. Rejection of rechallenge tumors was canceled only when both CD4+ and CD8+ T cells were removed in vivo, which indicates that each T-cell group functions independently in immunological memory. We show that ropeginterferon alfa-2b induces excellent antitumor immunomodulation in hosts. Our finding serves in devising therapeutic strategies with ropeginterferon alfa-2b.

    DOI: 10.1111/cas.15376

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  • TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment. 国際誌

    Shusuke Kawashima, Takashi Inozume, Masahito Kawazu, Toshihide Ueno, Joji Nagasaki, Etsuko Tanji, Akiko Honobe, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Tomonori Kawasaki, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Yuzuru Ikehara, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Hiroyuki Matsue, Yosuke Togashi

    Journal for immunotherapy of cancer   9 ( 11 )   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. METHODS: We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. RESULTS: Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. CONCLUSIONS: The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.

    DOI: 10.1136/jitc-2021-003134

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  • Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1. 国際誌

    Junji Koya, Yuki Saito, Takuro Kameda, Yasunori Kogure, Mitsuhiro Yuasa, Joji Nagasaki, Marni B McClure, Sumito Shingaki, Mariko Tabata, Yuki Tahira, Keiichi Akizuki, Ayako Kamiunten, Masaaki Sekine, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Akira Kitanaka, Nobuaki Nakano, Atae Utsunomiya, Yosuke Togashi, Seishi Ogawa, Kazuya Shimoda, Keisuke Kataoka

    Blood cancer discovery   2 ( 5 )   450 - 467   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)-infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1-infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell-restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis. SIGNIFICANCE: Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.

    DOI: 10.1158/2643-3230.BCD-21-0044

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  • The First Case of Non-leukemic Sarcoma Composed of Mixed-phenotype Acute Leukemia, B/myeloid, Not Otherwise Specified.

    Teruhito Takakuwa, Takahiko Nakane, Masahiko Ohsawa, Joji Nagasaki, Yasutaka Aoyama, Mistutaka Nishimoto, Yoshiki Hayashi, Yuko Kuwae, Masayuki Hino, Hirohisa Nakamae

    Internal medicine (Tokyo, Japan)   57 ( 8 )   1155 - 1158   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Isolated sarcoma with features of mixed-phenotype acute leukemia (MPAL) is an extremely rare disease and it can be easily misdiagnosed as lymphoma or other malignancies. We herein report the case of a 61-year-old woman with non-leukemic sarcoma of the right pleura, pretracheal lymph node, and supraclavicular lymph node with features of MPAL, B/myeloid, not otherwise specified, which was first misdiagnosed as diffuse large B cell lymphoma. After performing a detailed re-examination of the biopsy specimens, few scattered eosinophilic myelocytes allowed us to reach a correct diagnosis of MPAL and the patient was thereafter successfully treated by intensified chemotherapy followed by cord blood transplantation.

    DOI: 10.2169/internalmedicine.9144-17

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  • Pulmonary Involvement of Acute Myeloid Leukemia Mimicking Transfusion-related Acute Lung Injury.

    Kentaro Ido, Yasutaka Aoyama, Joji Nagasaki, Shiro Koh, Hiroyoshi Ichihara, Hiroshi Harada, Kiyoshi Kawano, Yoshihiko Tani, Nobuki Matsuyama, Fumiya Hirayama, Masatoshi Kohsaki, Shuji Takaku, Atsuko Mugitani

    Internal medicine (Tokyo, Japan)   56 ( 18 )   2493 - 2496   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Transfusion-related acute lung injury (TRALI) is defined as a new episode of acute lung injury (ALI) occurring during transfusion or within 6 hours of transfusion completion. A 66-year-old man suffering from acute myeloid leukemia developed acute respiratory distress syndrome after platelet transfusion. TRALI was diagnosed clinically, but an autopsy showed leukemic cells in diffuse pulmonary edema. Anti-human neutrophil antigen (HNA)-3a antibodies were detected in the donor serum, and the HNA-3 genotype of the patient was identified as a/a. This case was considered to represent pulmonary involvement of acute myeloid leukemia, rather than TRALI. A revision of the definition of TRALI accounting for hematological malignancies should therefore be considered.

    DOI: 10.2169/internalmedicine.8505-16

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  • Picture in Clinical Hematology(No.99) 末梢血塗抹標本で肺炎球菌の菌体を確認し得た形質細胞性白血病

    長崎 譲慈, 青山 泰孝, 改田 幸子, 井戸 健太郎, 市原 弘善, 畑中 重克, 太田 忠信, 麥谷 安津子

    臨床血液   58 ( 1 )   1 - 1   2017年1月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

    DOI: 10.11406/rinketsu.58.1

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  • Reversible dasatinib-related pulmonary arterial hypertension in a CML patient.

    Joji Nagasaki, Yasutaka Aoyama, Yuta Nomoto, Kentaro Ido, Hiroyoshi Ichihara, Atsuko Mugitani

    [Rinsho ketsueki] The Japanese journal of clinical hematology   57 ( 5 )   618 - 23   2016年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 59-year-old man diagnosed with the chronic phase of chronic myeloid leukemia (CML) in June 2011 was started on dasatinib (100 mg/day). He had no signs of pleural effusion (PE) or right heart failure before treatment, but symptoms of PE and dyspnea (New York Heart Association class III) appeared in January 2013 and May 2014, respectively. Doppler transthoracic echocardiography and right heart catheterization revealed pulmonary arterial hypertension (PAH) with an estimated pulmonary artery systolic pressure (PASP) of 80 mmHg and estimated mean pulmonary artery pressure of 29 mmHg. Rheumatoid factor, antinuclear antibody, dsDNA antibody, and SCL70 were not elevated, and computed tomography confirmed the absence of a pulmonary embolism. Therefore, dasatinib-related PAH was diagnosed and treatment with this agent was discontinued. The PASP had decreased to 51 and 40 mmHg at one month and one year, respectively, after dasatinib discontinuation. This patient developed PAH while receiving dasatinib administration and only discontinuation of this agent improved his symptoms. The possibility that dasatinib can cause PAH must be considered before administering this agent to patients with CML.

    DOI: 10.11406/rinketsu.57.618

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  • Postinfluenza Vaccination Idiopathic Thrombocytopenic Purpura in Three Elderly Patients. 国際誌

    Joji Nagasaki, Masahiro Manabe, Kentaro Ido, Hiroyoshi Ichihara, Yasutaka Aoyama, Tadanobu Ohta, Yoshio Furukawa, Atsuko Mugitani

    Case reports in hematology   2016   7913092 - 7913092   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The etiologies of secondary idiopathic thrombocytopenic purpura (ITP) include infection, autoimmune disease, and immunodeficiency. We report the cases of three elderly patients who developed ITP after receiving influenza vaccinations. The platelet count of an 81-year-old woman fell to 27,000/μL after she received an influenza vaccination. A 75-year-old woman developed thrombocytopenia (5,000 platelets/μL) after receiving an influenza vaccination. An 87-year-old woman whose laboratory test values included a platelet count of 2,000/μL experienced genital bleeding after receiving an influenza vaccination. After Helicobacter pylori (HP) eradication or corticosteroid treatment, all of the patients' platelet counts increased. Influenza vaccination is an underlying etiology of ITP in elderly patients. HP eradication or corticosteroid treatment is effective for these patients. Clinicians should be aware of the association between ITP and influenza vaccinations.

    DOI: 10.1155/2016/7913092

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  • Plasma Levels of Presepsin (Soluble CD14-subtype) as a Novel Prognostic Marker for Hemophagocytic Syndrome in Hematological Malignancies.

    Satoru Nanno, Hideo Koh, Takako Katayama, Masamichi Hashiba, Ayumi Sato, Yosuke Makuuchi, Joji Nagasaki, Masatomo Kuno, Takuro Yoshimura, Hiroshi Okamura, Mitsutaka Nishimoto, Asao Hirose, Mika Nakamae, Takahiko Nakane, Masayuki Hino, Hirohisa Nakamae

    Internal medicine (Tokyo, Japan)   55 ( 16 )   2173 - 84   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective Recent studies suggest that presepsin (soluble CD14-subtype) is a useful diagnostic and prognostic marker for sepsis, with secretion by activated macrophages potentially dependent on phagocytosis of microorganisms. As "hemophagocytosis" is one of the major characteristics in patients with hemophagocytic syndrome (HPS), we hypothesized that presepsin may reflect the phagocytic activity and be a useful prognostic marker for HPS. Therefore, we aimed to assess the prognostic potential of presepsin in secondary HPS in adult patients with hematological malignancies. Methods Between April 2006 and August 2014, we retrospectively examined consecutive patients with HPS whose blood samples were available at our institution and compared the prognostic value of the following in HPS, singly and in combination: plasma presepsin, serum soluble interleukin (IL)-2 receptor (sIL-2R), ferritin, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6 and IL-10. Results A total of 14 patients were enrolled. The median age of the patients was 46.5 years (range, 22-65). In univariable Cox models, there were no significant variables associated with the prognosis. However, in 12 evaluable patients, only the combination of higher median values of presepsin (>1,935 pg/mL) and sIL-2R (>4,585 U/mL) at the onset of HPS was significantly associated with the 90-day mortality (hazard ratio 14.5; 95% CI, 1.47-143.36; p=0.02). Conclusion These results suggest that a composite model of plasma presepsin and serum sIL-2R levels at the onset of HPS might be a novel predictor of the prognosis of patients with hematological malignancies and secondary HPS.

    DOI: 10.2169/internalmedicine.55.6524

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  • Optic Neuritis Associated with Myelodysplastic Syndrome Accompanied by Eosinophilic Crisis.

    Joji Nagasaki, Mitsutaka Nishimoto, Hirohisa Nakamae, Takahiko Nakane, Hideo Koh, Kumiko Yoshimoto, Kunihiko Shiraki, Masayuki Hino

    Internal medicine (Tokyo, Japan)   54 ( 17 )   2241 - 4   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myelodysplastic syndrome (MDS) was diagnosed in a 64-year-old man. Three months later, he presented with right-sided visual loss. A diagnosis of optic neuritis caused by both ischemic and non-ischemic changes was established. Concurrently, prominent eosinophilia was seen in both the peripheral blood and bone marrow. A partial improvement of visual loss was obtained concomitant with a rapid decrease of the eosinophils after treatment with corticosteroids. Optic neuritis related to MDS is a rare condition and its etiology has not yet been identified. We herein report a case of optic neuritis associated with MDS and accompanied by an eosinophilic crisis.

    DOI: 10.2169/internalmedicine.54.4148

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  • 免疫抑制療法後に急速に進行するEBV-LPDを発症した再生不良性貧血の症例

    長崎 譲慈, 朝田 裕貴, 細井 裕樹, 花岡 伸佳, 畑中 一生, 村田 祥吾, 島貫 栄弥, 栗本 美和, 園木 孝志, 中熊 秀喜

    臨床血液   52 ( 8 )   738 - 739   2011年8月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

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▼全件表示

書籍等出版物

MISC

  • Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    西日本泌尿器科学会総会抄録集   75回   185 - 185   2023年11月

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    記述言語:英語   出版者・発行元:(一社)西日本泌尿器科学会  

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  • 抗腫瘍免疫におけるインターフェロンγの役割と主要組織適合性遺伝子複合体の発現の重要性(Increasing MHC class I expression is crucial for antitumor immunity among IFNγ signaling pathways)

    川瀬 勝隆, 川島 秀介, 長崎 譲慈, 猪爪 隆史, 河津 正人, 花澤 豊行, 冨樫 庸介

    日本癌学会総会記事   82回   1020 - 1020   2023年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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講演・口頭発表等

  • Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    西日本泌尿器科学会総会抄録集  2023年11月  (一社)西日本泌尿器科学会

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    開催年月日: 2023年11月

    記述言語:英語  

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  • 抗腫瘍免疫におけるインターフェロンγの役割と主要組織適合性遺伝子複合体の発現の重要性(Increasing MHC class I expression is crucial for antitumor immunity among IFNγ signaling pathways)

    川瀬 勝隆, 川島 秀介, 長崎 譲慈, 猪爪 隆史, 河津 正人, 花澤 豊行, 冨樫 庸介

    日本癌学会総会記事  2023年9月  (一社)日本癌学会

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    開催年月日: 2023年9月

    記述言語:英語  

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  • 免疫プロファイリングによる、濾胞性リンパ腫の予後予測(Immune profiling analysis for prediction of outcome in patients with folliclular lymphoma)

    山内 寛彦, 湯田 淳一朗, 藤岡 優樹, 長崎 譲慈, 山崎 美貴, 冨樫 庸介, 南 陽介, 西川 博嘉

    臨床血液  2018年9月  (一社)日本血液学会-東京事務局

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    開催年月日: 2018年9月

    記述言語:英語  

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  • der(6)t(1;6)(q11;p21.3)を伴い骨髄線維化の進行を認めたMDS RARS-T

    長崎 譲慈, 井戸 健太郎, 市原 弘善, 青山 泰孝, 太田 忠信, 麥谷 安津子

    臨床血液  2016年11月  (一社)日本血液学会-東京事務局

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    開催年月日: 2016年11月

    記述言語:日本語  

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  • 可逆性のdasatinib関連肺動脈性高血圧症を発症した慢性骨髄性白血病

    長崎 譲慈, 井戸 健太郎, 市原 弘善, 青山 泰孝, 麥谷 安津子, 野本 陽太, 紙森 公雄

    臨床血液  2016年2月  (一社)日本血液学会-東京事務局

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    開催年月日: 2016年2月

    記述言語:日本語  

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  • 急性骨髄性白血病に対する血小板輸血中に呼吸窮迫を呈して死亡に至った1症例

    井戸 健太郎, 長崎 譲慈, 市原 弘善, 青山 泰孝, 麥谷 安津子

    臨床血液  2016年2月  (一社)日本血液学会-東京事務局

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    開催年月日: 2016年2月

    記述言語:日本語  

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  • 同種造血幹細胞移植後に骨髄線維化の改善を認めた骨髄線維症の2症例

    長崎 譲慈, 大北 淳也, 間部 賢寛, 古賀 裕規, 青山 泰孝, 麥谷 安津子

    臨床血液  2015年11月  (一社)日本血液学会-東京事務局

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    開催年月日: 2015年11月

    記述言語:日本語  

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  • 呼吸困難を伴う非溶血性輸血副作用症例の血小板製剤から検出されたHNA-3a抗体について

    入江 與利子, 尼岸 悦子, 松山 宣樹, 保井 一太, 三平 りさ, 唄野 直子, 麥谷 安津子, 青山 泰孝, 長崎 譲慈, 井戸 健太郎, 石井 博之, 松倉 晴道, 藤村 吉博, 平山 文也

    血液事業  2015年8月  日本血液事業学会

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    開催年月日: 2015年8月

    記述言語:日本語  

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  • インフルエンザワクチン接種後にITPを発症した3症例

    長崎 譲慈, 間部 賢寛, 大北 淳也, 古賀 裕規, 青山 泰孝, 久村 岳央, 麥谷 安津子

    臨床血液  2015年1月  (一社)日本血液学会-東京事務局

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    開催年月日: 2015年1月

    記述言語:日本語  

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  • トリソミー8を伴うMDS(RCMD)に合併した好酸球性視神経炎

    長崎 譲慈, 西本 光孝, 中根 孝彦, 康 秀男, 幕内 陽介, 康 史朗, 中前 博久, 日野 雅之

    臨床血液  2014年11月  (一社)日本血液学会-東京事務局

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    開催年月日: 2014年11月

    記述言語:日本語  

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  • 空腸・回腸悪性リンパ腫症例の後方視的解析

    湯川 芳美, 小柴 良司, 久松 美友紀, 間島 行則, 平位 暢康, 益岡 優, 上田 栄寿, 中島 ひろみ, 半野 元, 武田 修身, 高柳 成徳, 廣岡 知臣, 大北 淳也, 原田 尚憲, 長崎 譲慈, 間部 賢寛, 青山 泰孝, 久村 岳央, 麦谷 安津子, 土細工 利夫

    日本消化器病学会雑誌  2014年9月  (一財)日本消化器病学会

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    開催年月日: 2014年9月

    記述言語:日本語  

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  • 尿管圧迫を伴う悪性リンパ腫に対する尿管ステント留置の有効性

    間部 賢寛, 大北 淳也, 長崎 譲慈, 原田 尚憲, 青山 泰孝, 久村 岳央, 太田 忠信, 古川 佳央, 麦谷 安津子

    日本緩和医療学会学術大会プログラム・抄録集  2014年6月  (NPO)日本緩和医療学会

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    開催年月日: 2014年6月

    記述言語:日本語  

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  • 派生染色体der(16)t(1;16)を伴った多発性骨髄腫の3例

    間部 賢寛, 大北 淳也, 長崎 譲慈, 原田 尚憲, 青山 泰孝, 久村 岳央, 太田 忠信, 古川 佳央, 麦谷 安津子

    日本検査血液学会雑誌  2014年6月  (一社)日本検査血液学会

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    開催年月日: 2014年6月

    記述言語:日本語  

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  • 免疫抑制療法後に急速に進行するEBV-LPDを発症した再生不良性貧血の症例

    長崎 譲慈, 朝田 裕貴, 細井 裕樹, 花岡 伸佳, 畑中 一生, 村田 祥吾, 島貫 栄弥, 栗本 美和, 園木 孝志, 中熊 秀喜

    臨床血液  2011年8月  (一社)日本血液学会-東京事務局

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    開催年月日: 2011年8月

    記述言語:日本語  

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▼全件表示

共同研究・競争的資金等の研究

  • 腫瘍微小環境のゲノム異常とクローン性造血の関係解明

    研究課題/領域番号:23KK0149  2023年09月 - 2027年03月

    日本学術振興会  科学研究費助成事業  国際共同研究加速基金(海外連携研究)

    冨樫 庸介, 長崎 譲慈, 諏澤 憲

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    配分額:20800000円 ( 直接経費:16000000円 、 間接経費:4800000円 )

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  • 濾胞性ヘルパーT細胞の二面性に基づく悪性リンパ腫の腫瘍微小環境の本態解明

    研究課題/領域番号:23K14594  2023年04月 - 2025年03月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    長崎 譲慈

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

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  • 新規プロテオゲノミクス技術を応用した真のネオ抗原探索とそのバイオマーカー・治療への応用

    研究課題/領域番号:23ama221324h0001  2023年 - 2024年

    日本医療研究開発機構(AMED) 次世代がん医療加速化研究事業(P-PROMOTE)

    長崎 譲慈

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  • 腫瘍微小環境のexhausted CD4陽性T細胞の本態解明

    研究課題/領域番号:22K20824  2022年08月 - 2024年03月

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    長崎 譲慈

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    配分額:2860000円 ( 直接経費:2200000円 、 間接経費:660000円 )

    Exhausted CD4陽性T細胞を詳細に解析しCD4陽性T細胞の抗腫瘍免疫応答での新しい役割を基礎・臨床の両面から明らかにすることを目的に研究を遂行する。
    令和4年度の本研究の概要として、独自に見出したexhausted CD4陽性T細胞の抗腫瘍免疫応答での役割を基礎・臨床の両面から明らかにするために、まずはin vitroでexhausted CD4陽性T細胞の腫瘍特異性の検証を行った。シングルセルシークエンスで同定したTCRをT細胞株に遺伝子導入し、患者由来腫瘍細胞株との反応性を検証することで、同定したexhausted CD4陽性T細胞が腫瘍特異的であることを示した。
    さらにin vivoで担がんマウスのTILのフローサイトメトリーを用いた解析やin vitroでの機能解析を行うことで、exhausted CD4陽性T細胞の表現系や性質の評価を行った。これらとシングルセルシークエンスの結果からexhausted CD4陽性T細胞は2群に大別できることを見出しており、今後これら2つの細胞集団の特徴を、典型的な遺伝子をT細胞に遺伝子導入し、各細胞の機能の検証を行う。
    上記の結果はexhausted CD4陽性T細胞ががん免疫へ関与している可能性を示唆するものであり、その本態解明を継続して行う。

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