Updated on 2022/03/31

写真a

 
SUGIYAMA Daisuke
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division for Advanced Medical Research Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor

Degree 1

  1. 医学博士 ( 2015.3   大阪大学 ) 

Research Areas 2

  1. Life Science / Immunology

  2. Life Science / Immunology

Research History 4

  1. Graduate School of Medicine, Nagoya University   Department of Immunology   Assistant Professor

    2020.5

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    Country:Japan

  2. Graduate School of Medicine, Nagoya University   Department of Immunology   Designated assistant professor

    2018.4 - 2020.4

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    Country:Japan

  3. Graduate School of Medicine, Nagoya University   Department of Immunology   Researcher

    2016.4 - 2018.3

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    Country:Japan

  4. National Cancer Center   Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center   Researcher

    2015.4 - 2016.3

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    Country:Japan

Education 1

  1. Osaka University   Graduate School, Division of Medical Sciences

    2011.4 - 2015.3

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    Country: Japan

Professional Memberships 3

  1. 日本がん免疫学会

  2. 日本免疫学会

  3. 日本癌学会

 

Papers 29

  1. Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade.

    Miyai Y, Sugiyama D, Hase T, Asai N, Taki T, Nishida K, Fukui T, Chen-Yoshikawa TF, Kobayashi H, Mii S, Shiraki Y, Hasegawa Y, Nishikawa H, Ando Y, Takahashi M, Enomoto A

    Life science alliance   Vol. 5 ( 6 )   2022.6

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    Language:English   Publisher:Life science alliance  

    Cancer-associated fibroblasts (CAFs) are an integral component of the tumor microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumor response to ICB therapy has not been defined. Here, we show that a recently defined CAF subset characterized by the expression of Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favorable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs was positively correlated with CD4-positive T-cell infiltration and vascularization within non-small cell lung cancer tumors. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in syngeneic tumors in mice, respectively. These findings suggest the presence of a CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.

    DOI: 10.26508/lsa.202101230

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  2. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

    Kumagai Shogo, Koyama Shohei, Itahashi Kota, Tanegashima Tokiyoshi, Lin Yi-tzu, Togashi Yosuke, Kamada Takahiro, Irie Takuma, Okumura Genki, Kono Hidetoshi, Ito Daisuke, Fujii Rika, Watanabe Sho, Sai Atsuo, Fukuoka Shota, Sugiyama Eri, Watanabe Go, Owari Takuya, Nishinakamura Hitomi, Sugiyama Daisuke, Maeda Yuka, Kawazoe Akihito, Yukami Hiroki, Chida Keigo, Ohara Yuuki, Yoshida Tatsuya, Shinno Yuki, Takeyasu Yuki, Shirasawa Masayuki, Nakama Kenta, Aokage Keiju, Suzuki Jun, Ishii Genichiro, Kuwata Takeshi, Sakamoto Naoya, Kawazu Masahito, Ueno Toshihide, Mori Taisuke, Yamazaki Naoya, Tsuboi Masahiro, Yatabe Yasushi, Kinoshita Takahiro, Doi Toshihiko, Shitara Kohei, Mano Hiroyuki, Nishikawa Hiroyoshi

    CANCER CELL   Vol. 40 ( 2 ) page: 201 - +   2022.2

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    Language:Japanese   Publisher:Cancer Cell  

    The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

    DOI: 10.1016/j.ccell.2022.01.001

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  3. Depletion of central memory CD8(+) T cells might impede the antitumor therapeutic effect of Mogamulizumab

    Maeda Yuka, Wada Hisashi, Sugiyama Daisuke, Saito Takuro, Irie Takuma, Itahashi Kota, Minoura Kodai, Suzuki Susumu, Kojima Takashi, Kakimi Kazuhiro, Nakajima Jun, Funakoshi Takeru, Iida Shinsuke, Oka Mikio, Shimamura Teppei, Doi Toshihiko, Doki Yuichiro, Nakayama Eiichi, Ueda Ryuzo, Nishikawa Hiroyoshi

    NATURE COMMUNICATIONS   Vol. 12 ( 1 ) page: 7280   2021.12

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    Language:Japanese   Publisher:Nature Communications  

    Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.

    DOI: 10.1038/s41467-021-27574-0

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  4. Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia

    Fujioka Yuki, Sugiyama Daisuke, Matsumura Itaru, Minami Yosuke, Miura Masatomo, Atsuta Yoshiko, Ohtake Shigeki, Kiyoi Hitoshi, Miyazaki Yasushi, Nishikawa Hiroyoshi, Takahashi Naoto

    CANCERS   Vol. 13 ( 23 )   2021.12

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    Language:Japanese   Publisher:Cancers  

    Treatment-free remission (TFR) has become a therapeutic goal in chronic myeloid leukemia (CML), and approximately half of the patients with chronic phase-CML (CML-CP) with deep molecular remission (DMR) by tyrosine-kinase inhibitors (TKIs) have achieved TFR. However, the mechanism of continuous TFR is still unclear, as there are “fluctuate” patients who have BCR–ABL-positive leukemia cells but do not observe obvious relapse. We focused on the immune response and conducted an immune analysis using clinical samples from the imatinib discontinuation study, JALSG-STIM213. The results showed that, in the group that maintained TFR for 3 years, changes in regulatory T (Treg) cells were observed early after stopping imatinib treatment. The effector Treg (eTreg) cells increased transiently at 1 month after stopping imatinib and then returned to baseline at 3 months after stopping imatinib treatment. There was no difference in the Treg phenotype, and CD8+ T cells in the TFR group were relatively activated. High concentrations of imatinib before stopping were negatively correlated with eTreg cells after stopping imatinib. These data suggest immunological involvement in the maintenance of the TFR, and that Treg cells after stopping imatinib might be a biomarker for TFR. Furthermore, high imatinib exposure may have a negative immunological impact on the continuous TFR.

    DOI: 10.3390/cancers13235904

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  5. Novel anti-GARP antibody DS-1055a augments anti-tumor immunity by depleting highly suppressive GARP(+) regulatory T cells

    Satoh Kazuki, Kobayashi Yoichi, Fujimaki Kaori, Hayashi Shinko, Ishida Saori, Sugiyama Daisuke, Sato Takahiko, Lim Kyungtaek, Miyamoto Megumi, Kozuma Shiho, Kadokura Michinori, Wakita Kenichi, Hata Masato, Hirahara Kazuki, Amano Masato, Watanabe Ichiro, Okamoto Atsushi, Tuettenberg Andrea, Jonuleit Helmut, Tanemura Atsushi, Maruyama Shoichi, Agatsuma Toshinori, Wada Teiji, Nishikawa Hiroyoshi

    INTERNATIONAL IMMUNOLOGY   Vol. 33 ( 8 ) page: 435 - 446   2021.8

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    Language:Japanese   Publisher:International Immunology  

    Regulatory T (Treg) cells, which are essential for maintaining self-tolerance, inhibit anti-tumor immunity, consequently hindering protective cancer immunosurveillance, and hampering effective anti-tumor immune responses in tumor-bearing hosts. Here, we show that depletion of Treg cells via targeting glycoprotein A repetitions predominant (GARP) induces effective anti-tumor immune responses. GARP was specifically expressed by highly suppressive Treg cells in the tumor microenvironment (TME) of multiple cancer types in humans. In the periphery, GARP was selectively induced in Treg cells, but not in effector T cells, by polyclonal stimulation. DS-1055a, a novel afucosylated anti-human GARP monoclonal antibody, efficiently depleted GARP+ Treg cells, leading to the activation of effector T cells. Moreover, DS-1055a decreased FoxP3+CD4+ T cells in the TME and exhibited remarkable anti-tumor activity in humanized mice bearing HT-29 tumors. We propose that DS-1055a is a new Treg-cell-targeted cancer immunotherapy agent with augmentation of anti-tumor immunity.

    DOI: 10.1093/intimm/dxab027

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  6. Anti-GARP antibody DS-1055a augments antitumor immunity by depleting highly suppressive GARP(+) regulatory T cells.

    Satoh Kazuki, Kobayashi Yoichi, Fujimaki Kaori, Hata Masato, Hayashi Shinko, Ishida Saori, Sugiyama Daisuke, Sato Takahiko, Kyungtaek Lim, Miyamoto Megumi, Kozuma Shiho, Kadokura Michinori, Wakita Kenichi, Hirahara Kazuki, Amano Masato, Watanabe Ichiro, Okamoto Atsushi, Tuettenberg Andrea, Jonuleit Helmut, Tanemura Atsushi, Maruyama Shoichi, Agatsuma Toshinori, Wada Teiji, Nishikawa Hiroyoshi

    CANCER RESEARCH   Vol. 81 ( 13 )   2021.7

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    Language:Japanese  

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  7. Newly emerged immunogenic neoantigens enable to break the resistance of immune checkpoint inhibitors.

    Sugiyama Daisuke, Muramatsu Tomoaki, Noguchi Takuro, Akatsuka Yoshiki, Nishikawa Hiroyoshi

    CANCER RESEARCH   Vol. 81 ( 13 )   2021.7

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  8. Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors.

    Kobayashi T, Iwama S, Sugiyama D, Yasuda Y, Okuji T, Ito M, Ito S, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Ito Y, Suga H, Banno R, Nishikawa H, Arima H

    Journal for immunotherapy of cancer   Vol. 9 ( 5 )   2021.5

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    Language:English   Publisher:Journal for ImmunoTherapy of Cancer  

    DOI: 10.1136/jitc-2021-002493

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  9. Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal

    Isoyama Sho, Mori Shigeyuki, Sugiyama Daisuke, Kojima Yasuhiro, Tada Yasuko, Shitara Kohei, Hinohara Kunihiko, Dan Shingo, Nishikawa Hiroyoshi

    JOURNAL FOR IMMUNOTHERAPY OF CANCER   Vol. 9 ( 8 )   2021

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    Language:Japanese   Publisher:Journal for ImmunoTherapy of Cancer  

    Background Immune checkpoint blockade (ICB) induces durable clinical responses in patients with various types of cancer. However, its limited clinical efficacy requires the development of better approaches. In addition to immune checkpoint molecules, tumor-infiltrating immunosuppressive cells including regulatory T cells (Tregs) play crucial roles in the immune suppressive tumor microenvironment. While phosphatidylinositol 3-kinase (PI3K) inhibition as a Treg-targeted treatment has been implicated in animal models, its effects on human Tregs and on the potential impairment of effector T cells are required to be clarified for successful cancer immunotherapy. Methods The impact of a selective-PI3K inhibitor ZSTK474 with or without anti-programmed cell death 1 (PD-1) monoclonal antibody on Tregs and CD8 + T cells were examined with in vivo animal models and in vitro experiments with antigen specific and non-specific fashions using peripheral blood from healthy individuals and cancer patients. Phenotypes and functions of Tregs and effector T cells were examined with comprehensive gene and protein expression assays. Results Improved antitumor effects by the PI3K inhibitor in combination with ICB, particularly PD-1 blockade, were observed in mice and humans. Although administration of the PI3K inhibitor at higher doses impaired activation of CD8 + T cells as well as Tregs, the optimization (doses and timing) of this combination treatment selectively decreased intratumoral Tregs, resulting in increased tumor antigen-specific CD8 + T cells in the treated mice. Moreover, on the administration of the PI3K inhibitor with the optimal dose for selectively deleting Tregs, PI3K signaling was inhibited not only in Tregs but also in activated CD8 + T cells, leading to the enhanced generation of tumor antigen-specific memory CD8 + T cells which contributed to durable antitumor immunity. These opposing outcomes between Tregs and CD8 + T cells were attributed to the high degree of dependence on T cell signaling in the former but not in the latter. Conclusions PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8 + T cell responses, illustrating a promising combination therapy.

    DOI: 10.1136/jitc-2020-002279

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  10. CD4<sup>+</sup> T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice.

    Yasuda Y, Iwama S, Sugiyama D, Okuji T, Kobayashi T, Ito M, Okada N, Enomoto A, Ito S, Yan Y, Sugiyama M, Onoue T, Tsunekawa T, Ito Y, Takagi H, Hagiwara D, Goto M, Suga H, Banno R, Takahashi M, Nishikawa H, Arima H

    Science translational medicine   Vol. 13 ( 593 )   2021.5

  11. Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer.

    Inamori K, Togashi Y, Fukuoka S, Akagi K, Ogasawara K, Irie T, Motooka D, Kobayashi Y, Sugiyama D, Kojima M, Shiiya N, Nakamura S, Maruyama S, Suzuki Y, Ito M, Nishikawa H

    JCI insight   Vol. 6 ( 9 )   2021.5

  12. Flow cytometry analysis of peripheral Tregs in patients with multiple myeloma under lenalidomide maintenance

    Nozaki Kenji, Fujioka Yuki, Sugiyama Daisuke, Ishikawa Jun, Iida Masato, Shibata Masaru, Kosugi Satoru, Nishikawa Hiroyoshi, Shibayama Hirohiko

    INTERNATIONAL JOURNAL OF HEMATOLOGY     2021.2

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    Publisher:International Journal of Hematology  

    DOI: 10.1007/s12185-021-03093-y

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  13. Development of novel combination cancer immunotherapy using anti-PD-1 and anti-PD-L1 antibody

    Hasegawa Hirotaka, Sugiyama Daisuke, Kanda Mitsuro, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Nomoto Shuji, Fujiwara Michitaka, Kodera Yasuhiro, Nishikawa Hiroyoshi

    CANCER SCIENCE   Vol. 112   page: 741 - 741   2021.2

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  14. A simple method to distinguish residual elotuzumab from monoclonal paraprotein in immunofixation assays for multiple myeloma patients

    Chen Shurui, Kiguchi Toru, Nagata Yasuyuki, Tamai Yotaro, Ikeda Takeshi, Kajiya Ryoko, Ono Takaaki, Sugiyama Daisuke, Nishikawa Hiroyoshi, Akatsuka Yoshiki

    INTERNATIONAL JOURNAL OF HEMATOLOGY     2021.1

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    Publisher:International Journal of Hematology  

    DOI: 10.1007/s12185-021-03088-9

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  15. Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T-cell-dependent manner.

    Muramatsu T, Noguchi T, Sugiyama D, Kanada Y, Fujimaki K, Ito S, Gotoh M, Nishikawa H

    International immunology   Vol. 33 ( 1 ) page: 39-48   2021.1

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    DOI: 10.1093/intimm/dxaa049

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  16. Endoscopic Activity and Serum TNF-alpha Level at Baseline Are Associated With Clinical Response to Ustekinumab in Crohn's Disease Patients

    Murate Kentaro, Maeda Keiko, Nakamura Masanao, Sugiyama Daisuke, Wada Hirotaka, Yamamura Takeshi, Sawada Tsunaki, Mizutani Yasuyuki, Ishikawa Takuya, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Miyahara Ryoji, Ishigami Masatoshi, Nishikawa Hiroyoshi, Fujishiro Mitsuhiro

    INFLAMMATORY BOWEL DISEASES   Vol. 26 ( 11 ) page: 1669 - 1681   2020.11

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    Publisher:Inflammatory Bowel Diseases  

    DOI: 10.1093/ibd/izaa086

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  17. The status of the tumor microenvironment changes dynamics of the balance of CD8(+) T cells and Treg cells in renal cell carcinoma

    Sugiyama Daisuke, Muramatsu Tomoaki, Kobayashi Yoichi, Sassa Naoto, Maruyama Shoichi, Goto Momokazu, Akatsuka Yoshiki, Nishikawa Hiroyoshi

    CANCER RESEARCH   Vol. 80 ( 16 )   2020.8

  18. The potential application of pd-1 blockade therapy for early-stage biliary tract cancer

    Umemoto K.

    International Immunology   Vol. 32 ( 4 ) page: 273 - 281   2020.4

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    Publisher:International Immunology  

    DOI: 10.1093/intimm/dxaa080

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  19. Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells.

    The Journal of experimental medicine   Vol. 217 ( 2 )   2020.2

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1084/jem.20191009

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  20. The potential application of PD-1 blockade therapy for early-stage biliary tract cancer.

    Umemoto K, Togashi Y, Arai Y, Nakamura H, Takahashi S, Tanegashima T, Kato M, Nishikawa T, Sugiyama D, Kojima M, Gotohda N, Kuwata T, Ikeda M, Shibata T, Nishikawa H

    International immunology     2019.12

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    DOI: 10.1093/intimm/dxz080

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  21. Selective inhibition of low-affinity memory CD8<sup>+</sup> T cells by corticosteroids.

    Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, Togashi Y, Sakai C, Wolchok JD, Nishikawa H

    The Journal of experimental medicine   Vol. 216 ( 12 ) page: 2701-2713   2019.12

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    DOI: 10.1084/jem.20190738

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  22. Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity

    Tanegashima Tokiyoshi, Togashi Yosuke, Azuma Koichi, Kawahara Akihiko, Ideguchi Ko, Sugiyama Daisuke, Kinoshita Fumio, Akiba Jun, Kashiwagi Eiji, Takeuchi Ario, Irie Takuma, Tatsugami Katsunori, Hoshino Tomoaki, Eto Masatoshi, Nishikawa Hiroyoshi

    CLINICAL CANCER RESEARCH   Vol. 25 ( 15 ) page: 4808-4819   2019.8

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    DOI: 10.1158/1078-0432.CCR-18-3991

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  23. Tumor-infiltrating lymphocytes in renal cancer patients demonstrate a diverse PD-1 expression and characteristic Treg classification

    Sugiyama Daisuke, Muramatsu Tomoaki, Kobayashi Yoichi, Sassa Naoto, Maruyama Shoichi, Goto Momokazu, Akatsuka Yoshiki, Nishikawa Hiroyoshi

    CANCER RESEARCH   Vol. 79 ( 13 )   2019.7

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    DOI: 10.1158/1538-7445.AM2019-4047

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  24. Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody

    Ha Danbee, Tanaka Atsushi, Kibayashi Tatsuya, Tanemura Atsushi, Sugiyama Daisuke, Wing James Badger, Lim Ee Lyn, Teng Karen Wei Weng, Adeegbe Dennis, Newell Evan W., Katayama Ichiro, Nishikawa Hiroyoshi, Sakaguchi Shimon

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 116 ( 2 ) page: 609-618   2019.1

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    DOI: 10.1073/pnas.1812186116

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  25. Immune suppressive mechanism of corticosteroids used for immune-related adverse events

    Maeda Yuka, Tokunaga Akihiro, Sugiyama Daisuke, Warner Allison B., Wolchok Jedd D., Nishikawa Hiroyoshi

    CANCER SCIENCE   Vol. 109   page: 1121-1121   2018.12

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  26. Immune-mediated antitumor effects of a pan PI3K inhibitor ZSTK474

    Isoyama Sho, Sugiyama Daisuke, Nishikawa Hiroyoshi

    CANCER SCIENCE   Vol. 109   page: 221-221   2018.12

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  27. 大腸癌における免疫学的な新たな分類と新規がん免疫療法の可能性

    冨樫 庸介, 稲守 宏治, 福岡 聖大, 杉山 大介, 伊藤 雅昭, 西川 博嘉

    日本がん免疫学会総会プログラム・抄録集   Vol. 22回   page: 83 - 83   2018.7

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  28. Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis

    Shitaoka Kiyomi, Hamana Hiroshi, Kishi Hiroyuki, Hayakawa Yoshihiro, Kobayashi Eiji, Sukegawa Kenta, Piao Xiuhong, Lyu Fulian, Nagata Takuya, Sugiyama Daisuke, Nishikawa Hiroyoshi, Tanemura Atsushi, Katayama Ichiro, Murahashi Mutsunori, Takamatsu Yasushi, Tani Kenzaburo, Ozawa Tatsuhiko, Muraguchi Atsushi

    CANCER IMMUNOLOGY RESEARCH   Vol. 6 ( 4 ) page: 378-388   2018.4

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    DOI: 10.1158/2326-6066.CIR-17-0489

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  29. Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation

    Doki Noriko, Suyama Masahiro, Sasajima Satoshi, Ota Junko, Igarashi Aiko, Mimura Iyo, Morita Hidetoshi, Fujioka Yuki, Sugiyama Daisuke, Nishikawa Hiroyoshi, Shimazu Yutaka, Suda Wataru, Takeshita Kozue, Atarashi Koji, Hattori Masahira, Sato Eiichi, Watakabe-Inamoto Kyoko, Yoshioka Kosuke, Najima Yuho, Kobayashi Takeshi, Kakihana Kazuhiko, Takahashi Naoto, Sakamaki Hisashi, Honda Kenya, Ohashi Kazuteru

    ANNALS OF HEMATOLOGY   Vol. 96 ( 9 ) page: 1517-1523   2017.9

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    DOI: 10.1007/s00277-017-3069-8

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Books 2

  1. 書名「新世代フローサイトメトリー活用スタンダード」 第1章 3項-1 マスサイトメトリーによる腫瘍浸潤リンパ球のマルチカラー解析

    ( Role: Contributor)

    羊土社 

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    Book type:Scholarly book

  2. 書名「創薬研究者・アカデミア研究者が知っておくべき 最新の免疫学とその応用技術」 第1章-第3節 創薬研究者が知っておくべき免疫抑制細胞の機能および最新研究動向

    ( Role: Contributor)

    技術情報協会 

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    Book type:Scholarly book

Presentations 1

  1. Immune responses against immunogenic neoantigens enable to break the resistance to immune checkpoint inhibitors

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    Language:English   Presentation type:Oral presentation (general)  

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. TRPV1シグナル活性化による新規がん免疫応答メカニズムの解明

    Grant number:19K16830  2019.4 - 2022.3

    若手研究

    杉山 大介

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    近年がんに対する免疫療法が注目を浴びており、とりわけ免疫チェックポイント阻害剤は目覚ましい治療効果を示している。一方で、免疫療法の恩恵を受けない患者も多く、免疫療法のさらなる改良が切望されている。本研究課題では、生体の感覚を伝達する受容体であるTRPV1に着目し、TRPV1シグナルの活性化によるがん免疫応答増強メカニズムの解明を試みる。TRPV1シグナルは免疫細胞活性化に加え、がん細胞への直接的殺傷効果も期待できる。本研究成果より、がん免疫応答の新たな分子メカニズムが解明されることで、がん免疫療法の効果を向上させる新規治療法の開発につながると考えられる。
    本研究では、温度センサーの一種であるTRPV1受容体の作用に着目し、TRPV1シグナルによる炎症誘導ががん免疫応答を向上させるメカニズムを解明し、免疫チェックポイント阻害剤の治療効果を増強できる因子を見出すことを目的とする。本年度は主にマウス大腸癌細胞株MC38と肺癌細胞株LLCの2種類のがん細胞株を用いた検討をおこなった。初めに、TRPV1シグナル伝達による直接的な癌細胞殺傷効果を検討するため、細胞株にTRPV1のアゴニストであるカプサイシンを作用させたところ、一定の細胞殺傷効果を示すことが分かった。さらに、抗PD-1抗体治療効果が見られない投与タイミングにてTRPV1のアゴニストであるカプサイシンを使用することで抗PD-1抗体治療による腫瘍退縮効果を発揮できることを示した。また、がん細胞株を生着させたマウスにカプサイシンを作用させ、脾臓・リンパ節・腫瘍組織から免疫細胞を回収し、TRPV1シグナル伝達による各種免疫細胞動態変化をフローサイトメトリー法により解析した。その結果、リンパ節および腫瘍組織に浸潤する樹状細胞が活性化していることが分かった。TRPV1シグナル伝達の作用がヒト免疫系における影響を検討するため、健康人末梢血単核球から樹状細胞を誘導し、カプサイシンを作用させたところ、活性化分子発現の増強が確認できた。これらの研究成果から、TRPV1シグナル伝達による免疫系の向上効果はヒトおよびマウスの両方においても確認できたため、マウスモデルにおいてがん免疫応答におけるTRPV1シグナルの作用メカニズムを解明することで、ヒトに応用できる可能性が強く示唆された。
    今年度は、2種類の癌細胞株を用いた検討によりTRPV1シグナル伝達による免疫応答向上効果が抗PD-1抗体治療効果を増強できることを示した。これによりTRPV1シグナル伝達と抗PD-1抗体治療との併用効果が広く利用できる可能性がある。さらに、TRPV1シグナル伝達による免疫系の変化を解析したところ、樹状細胞の活性化が誘導されることを見出し、TRPV1シグナル伝達によるがん免疫応答の向上に起因する主要免疫細胞を特定することができた。また、ヒト樹状細胞においてもTRPV1シグナル伝達により活性化されることを見出すことができ、本研究課題がヒトに臨床応用できる可能性を強く示唆できる実験成果を得た。これらの実験結果から、TRPV1シグナル伝達による免疫応答変化フェノタイプを見出すことができたため、来年度ではこの免疫応答変化の分子メカニズム解明のための遺伝子解析およびタンパク質発現解析実験に移行することができる。
    今後の研究展望として、今年度に見出したTRPV1シグナル伝達による樹状細胞活性化における分子メカニズムの解明を進める。カプサイシンを作用させた担癌マウスのリンパ節および腫瘍組織から樹状細胞を回収し、RNAを抽出・精製する。得られたRNAを用いたRNAシーケンス解析を実施し、TRPV1シグナル伝達により発現上昇する遺伝子群を見出し、樹状細胞活性化に起因する遺伝子を同定する。本RNAシーケンス解析をヒト樹状細胞においても実施し、ヒトおよびマウスにて共通する遺伝子を選定する。選定した遺伝子について、リアルタイムPCR法およびフローサイトメトリー解析を実施することで、TRPV1シグナル伝達により選定した遺伝子およびそのタンパク質が発現上昇することを確認する。これらの実験結果から、TRPV1シグナル伝達により活性化する免疫系において重要な因子を同定し、その因子を標的とした新規治療法の開発に向けたPOC確立を目指す。

  2. Identification of new molecule for regulatory T cells in an anti-tumor immunity

    Grant number:15H06880  2015.8 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    Sugiyama Daisuke, Nishikawa Hiroyoshi, Doi Toshihiko

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    A cancer immunotherapy using the immune systems attracts attention as a therapeutic method to novel cancer therapy. In this study, we analyzed immune responses of the stomach-cancer patient and was intended that we got knowledge to be connected for development of the new cancer immunotherapy.
    After analyzing the immune cells in a blood or tumor tissue of the stomach cancer patients, there were more ratios of regulatory T cells which suppressed anti-tumor immune responses in the tumor tissues than blood, and they highly expressed cell surface molecules such as ICOS or CTLA-4. From these results, we suggested that expect an improvement effect of the anti-tumor immune responses by the removal of the regulatory T cells by ICOS and CTLA-4 marker.

 

Teaching Experience (On-campus) 1

  1. Immunology and Host Defense System

    2021