KEIO RESEARCHERS INFORMATION SYSTEM

Profile 【 Display / hide 】

Profile 【 Display / hide 】

• Yuki Kagoya received his MD at the University of Tokyo in 2007 and completed clinical training for Internal Medicine, Hematology & Medical Oncology, and Transplantation Medicine. Dr. Kagoya was then involved in basic research on leukemia initiating cells during his PhD training. After obtaining PhD, he joined Dr. Naoto Hirano’s laboratory at Princess Margaret Cancer Centre, Toronto to be dedicated to research on cancer immunology and immunotherapy (2014-2018). He served on Aichi Cancer Center Research Institute as the Principal Investigator for 3 years prior to his recruitment to Keio University.

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2007.04

  -

  2009.03

  Kanto Rosai Hospital, 内科

• 2013.04

  -

  2013.09

  The University of Tokyo, Faculty of Medicine University Hospital Heamatology and Oncology, Research Fellow

• 2013.10

  -

  2014.05

  The University of Tokyo, Faculty of Medicine University Hospital Heamatology and Oncology, Assistant Professor

• 2014.06

  -

  2018.05

  Princess Margaret Cancer Centre, Tumor Immunotherapy Program, Research Fellow

• 2018.06

  -

  2019.09

  The University of Tokyo, Faculty of Medicine University Hospital, Assistant Professor

display all >>

Academic Background 【 Display / hide 】

Academic Background 【 Display / hide 】

• 2001.04

  -

  2007.03

  The University of Tokyo, Faculty of Medicine, 医学科

• 2009.04

  -

  2013.03

  The University of Tokyo, Graduate School of Medicine

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• Ph.D., The University of Tokyo, Coursework, 2013.03

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Immunology (cancer immunology; cancer immunotherapy; cell therapy; molecular cell biology, hematology and medical oncology)

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• CD83 expression characterizes precursor exhausted T cell population

  Zhiwen Wu, Toshiaki Yoshikawa, Satoshi Inoue, Yusuke Ito, Hitomi Kasuya, Takahiro Nakashima, Haosong Zhang, Saki Kotaka, Waki Hosoda, Shiro Suzuki, Yuki Kagoya

  Communications Biology 6 （ 1 ） 258 2023.03

  Research paper (scientific journal), Last author, Corresponding author, Accepted

  　View Summary

  T cell exhaustion is a main obstacle against effective cancer immunotherapy. Exhausted T cells include a subpopulation that maintains proliferative capacity, referred to as precursor exhausted T cells (TPEX). While functionally distinct and important for antitumor immunity, TPEX possess some overlapping phenotypic features with the other T-cell subsets within the heterogeneous tumor-infiltrating T-lymphocytes (TIL). Here we explore surface marker profiles unique to TPEX using the tumor models treated by chimeric antigen receptor (CAR)-engineered T cells. We find that CD83 is predominantly expressed in the CCR7+PD1+ intratumoral CAR-T cells compared with the CCR7-PD1+ (terminally differentiated) and CAR-negative (bystander) T cells. The CD83+CCR7+ CAR-T cells exhibit superior antigen-induced proliferation and IL-2 production compared with the CD83- T cells. Moreover, we confirm selective expression of CD83 in the CCR7+PD1+ T-cell population in primary TIL samples. Our findings identify CD83 as a marker to discriminate TPEX from terminally exhausted and bystander TIL.

  • Access to Document (DOI)

• Genetic ablation of PRDM1 in antitumor T cells enhances therapeutic efficacy of adoptive immunotherapy

  Toshiaki Yoshikawa, Zhiwen Wu, Satoshi Inoue, Hitomi Kasuya, Hirokazu Matsushita, Yusuke Takahashi, Hiroaki Kuroda, Waki Hosoda, Shiro Suzuki, Yuki Kagoya

  Blood （American Society of Hematology)  139 （ 14 ） 2156 - 2172 2022.04

  Last author, Corresponding author, Accepted,  ISSN  0006-4971

  　View Summary

  Adoptive cancer immunotherapy can induce objective clinical efficacy in patients with advanced cancer; however, a sustained response is achieved in a minority of cases. The persistence of infused T cells is an essential determinant of a durable therapeutic response. Antitumor T cells undergo a genome-wide remodeling of the epigenetic architecture upon repeated antigen encounters, which inevitably induces progressive T-cell differentiation and the loss of longevity. In this study, we identified PR domain zinc finger protein 1 (PRDM1) ie, Blimp-1, as a key epigenetic gene associated with terminal T-cell differentiation. The genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion in repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells. PRDM1 disruption promoted the expansion of less differentiated memory CAR-T cells in vivo, which enhanced T-cell persistence and improved therapeutic efficacy in multiple tumor models. Mechanistically, PRDM1-ablated T cells displayed enhanced chromatin accessibility of the genes that regulate memory formation, thereby leading to the acquisition of gene expression profiles representative of early memory T cells. PRDM1 knockout also facilitated maintaining an early memory phenotype and cytokine polyfunctionality in T-cell receptor-engineered T cells as well as tumor-infiltrating lymphocytes. In other words, targeting PRDM1 enabled the generation of superior antitumor T cells, which is potentially applicable to a wide range of adoptive cancer immunotherapies.

  • Access to Document (DOI)

• CAMK2G is identified as a novel therapeutic target for myelofibrosis

  Masashi Miyauchi, Ken Sasaki, Yuki Kagoya, Kazuki Taoka, Yosuke Masamoto, Sho Yamazaki, Shunya Arai, Hideaki Mizuno, Mineo Kurokawa

  Blood Advances （American Society of Hematology)  6 （ 5 ） 1585 - 1597 2022.03

  Accepted,  ISSN  2473-9529

  　View Summary

  Although JAK1/2 inhibition is effective in alleviating symptoms of myelofibrosis (MF), it does not result in the eradication of MF clones, which can lead to inhibitor-resistant clones emerging during the treatment. Here, we established induced pluripotent stem cells (iPSCs) derived from MF patient samples (MF-iPSCs) harboring JAK2 V617F, CALR type 1, or CALR type 2 mutations. We demonstrated that these cells faithfully recapitulate the drug sensitivity of the disease. These cells were used for chemical screening, and calcium/calmodulin-dependent protein kinase 2 (CAMK2) was identified as a promising therapeutic target. MF model cells and mice induced by MPL W515L, another type of mutation recurrently detected in MF patients, were used to elucidate the therapeutic potential of CAMK2 inhibition. CAMK2 inhibition was effective against JAK2 inhibitor-sensitive and JAK2 inhibitor-resistant cells. Further research revealed CAMK2 γ subtype was important in MF model cells induced by MPL W515L. We showed that CAMK2G hetero knockout in the primary bone marrow cells expressing MPL W515L decreased colony-forming capacity. CAMK2G inhibition with berbamine, a CAMK2G inhibitor, significantly prolonged survival and reduced disease phenotypes, such as splenomegaly and leukocytosis in a MF mouse model induced by MPL W515L. We investigated the molecular mechanisms underlying the therapeutic effect of CAMK2G inhibition and found that CAMK2G is activated by MPL signaling in MF model cells and is an effector in the MPL-JAK2 signaling pathway in these cells. These results indicate CAMK2G plays an important role in MF, and CAMK2G inhibition may be a novel therapeutic strategy that overcomes resistance to JAK1/2 inhibition.

  • Access to Document (DOI)

• CD62L expression level determines the cell fate of myeloid progenitors

  Yusuke Ito, Fumio Nakahara, Yuki Kagoya, Mineo Kurokawa

  Stem Cell Reports （Elsevier BV)  16 （ 12 ） 2871 - 2886 2021.12

  Accepted,  ISSN  2213-6711

  　View Summary

  Hematopoietic cells differentiate through several progenitors in a hierarchical manner, and recent single-cell analyses have revealed substantial heterogeneity within each progenitor. Although common myeloid progenitors (CMPs) are defined as a multipotent cell population that can differentiate into granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs), and GMPs generate neutrophils and monocytes, these myeloid progenitors must contain some lineage-committed progenitors. Through gene expression analysis at single-cell levels, we identified CD62L as a marker to reveal the heterogeneity. We confirmed that CD62L-negative CMPs represent "bona fide" CMPs, whereas CD62L-high CMPs are mostly restricted to GMP potentials both in mice and humans. In addition, we identified CD62L-negative GMPs as the most immature subsets in GMPs and Ly6C+CD62L-intermediate and Ly6C+CD62L-high GMPs are skewed to neutrophil and monocyte differentiation in mice, respectively. Our findings contribute to more profound understanding about the mechanism of myeloid differentiation.

  • Access to Document (DOI)

• Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation

  Hideaki Mizuno, Junji Koya, Yosuke Masamoto, Yuki Kagoya, Mineo Kurokawa

  Cancer Science （Wiley)  112 （ 10 ） 4112 - 4126 2021.10

  Accepted,  ISSN  1347-9032

  　View Summary

  Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.

  • Access to Document (DOI)

display all >>

Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

  Yusuke Ito, Yuki Kagoya

  Cancer Science 113 ( 11 ) 3664 - 3671 2022.11

  Corresponding author

  　View Summary

  Recent advancements in cancer immunotherapy, such as chimeric antigen receptor (CAR)-engineered T cell therapy and immune checkpoint therapy, have significantly improved the clinical outcomes of patients with several types of cancer. To broaden its applicability further and induce durable therapeutic efficacy, it is imperative to understand how antitumor T cells elicit cytotoxic functions, survive as memory T cells, or are impaired in their effector functions (exhausted) at the molecular level. T cell properties are regulated by their gene expression profiles, which are further controlled by epigenetic architectures, such as DNA methylation and histone modifications. Multiple studies have elucidated specific epigenetic genes associated with T-cell phenotypic changes. Conversely, exogenous modification of these key epigenetic factors can significantly alter T cell functions by extensively altering the transcription network, which can be applied in cancer immunotherapy by improving T cell persistence or augmenting effector functions. As CAR-T cell therapy involves a genetic engineering step during the preparation of the infusion products, it would be a feasible strategy to additionally modulate specific epigenetic genes in CAR-T cells to improve their quality. Here, we review recent studies investigating how individual epigenetic factors play a crucial role in T-cell biology. We further discuss future directions to integrate these findings for optimal cancer immunotherapy.

• Dissecting the heterogeneity of exhausted T cells at the molecular level.

  Yuki Kagoya

  International Immunolology 34 ( 11 ) 547 - 553 2022.10

  Lead author, Last author, Corresponding author

  　View Summary

  Our understanding of mechanisms underlying T-cell exhaustion has been refined by analysis of exhausted T cells at the molecular level. The development and functions of exhausted T cells are regulated by a number of transcription factors, epigenetic factors and metabolic enzymes. In addition, recent work to dissect exhausted T cells at the single-cell level has enabled us to discover a precursor exhausted T-cell subset equipped with long-term survival capacity. Starting from the analysis of mouse models, the existence of precursor exhausted T cells has also been documented in human T cells in the context of chronic virus infections or tumors. Clinical data suggest that evaluating the quality of exhausted T cells on the basis of their differentiation status may be helpful to predict the therapeutic response to inhibition of programmed death 1 (PD1). Moreover, beyond immune-checkpoint blockade, novel therapeutic approaches to re-invigorate exhausted T cells have been explored based on molecular insights into T-cell exhaustion. Here I will discuss key molecular profiles associated with the development, maintenance and differentiation of exhausted T cells and how these findings can be applicable in the field of cancer immunotherapy.

• Regulation of leukemia initiating cells by NF-κB signaling

  籠谷 勇紀

  血液内科 (科学評論社)  70 ( 3 ) 373 - 378 2015.03

  ISSN  2185-582X

Presentations 【 Display / hide 】

Presentations 【 Display / hide 】

• Development of next-generation CAR-T cell therapy

  Yuki Kagoya

  第6回バイオ医薬EXPO, 

  2022.07

  , 

  Oral presentation (invited, special)

• CAR-T 細胞療法の適用拡大に向けた研究開発

  籠谷 勇紀

  第7回日本がんサポーティブケア学会学術集会, 

  2022.06

  , 

  Oral presentation (invited, special)

• エピジェネティクス改変による長期生存型CAR-T細胞の製造

  籠谷 勇紀

  第14回日本血液疾患免疫療法学会, 

  2022.06

  , 

  Oral presentation (invited, special)

• エピジェネティクス修飾によるCAR-T細胞の改良

  籠谷 勇紀

  第3回東京理科大学総合研究院合成生物学研究部門シンポジウム, 

  2022.03

  , 

  Oral presentation (invited, special)

• Genetic modification of antitumor T cells for optimal adoptive cancer immunotherapy

  Franco-Japanese immuno-oncology webinar series, 

  2022.03

  , 

  Oral presentation (invited, special)

display all >>

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

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

• Development of CAR-NK cell therapy with durable response through genetic manipulation

  2023.04

  -

  2026.03

  基盤研究(B), Principal investigator

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• ADVANCED MEDICAL RESEARCH: SEMINAR

  2023

• ADVANCED MEDICAL RESEARCH: PRACTICE

  2023

• ADVANCED MEDICAL RESEARCH

  2023

• ADVANCED MEDICAL RESEARCH

  2023