Degree 【 display / non-display 】

Degree 【 display / non-display 】

• MD/PhD

Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2022.06

  -

  Now

  Sapporo Medical University   附属研究所 免疫プロテオゲノミクス共同研究拠点  

• 2016

  -

  Now

  Sapporo Medical University   病理学第一講座   Assistant Professor

• 2012

  -

  2015

  Sapporo Medical University   病理学第一講座   助教

• 2008

  -

  2011

  日本学術振興会   特別研究員

• 2002

  -

  2008

  カリフォルニア州立大学バークレー校・免疫学部門   研究員

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Immunology   CANCER IMMUNOLOGY

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• Immunopeptidome

• T cell

• Tumor antigen

• Cancer Immunotherapy

• scRNA-seq

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Proteogenomic identification of an immunogenic antigen derived from human endogenous retrovirus in renal cell carcinoma.

  Shin Kobayashi, Serina Tokita, Keigo Moniwa, Katsuyuki Kitahara, Hiromichi Iuchi, Kazuhiko Matsuo, Hidehiro Kakizaki, Takayuki Kanaseki, Toshihiko Torigoe

  JCI insight   8 ( 16 )  2023.08  [International journal]

  Authorship：   Corresponding author

  　View Summary

  CD8+ T cells can recognize tumor antigens displayed by HLA class I molecules and eliminate tumor cells. Despite their low tumor mutation burden, immune checkpoint blockade (ICB) is often beneficial in patients with renal cell carcinoma (RCC). Here, using a proteogenomic approach, we directly and comprehensively explored the HLA class I-presenting peptidome of RCC tissues and demonstrated that the immunopeptidomes contain a small subset of peptides derived from human endogenous retroviruses (hERV). A comparison between tumor and normal kidney tissues revealed tumor-associated hERV antigens, one of which was immunogenic and recognized by host tumor-infiltrating lymphocytes (TIL). Stimulation with the hERV antigen induced reactive CD8+ T cells in healthy donor-derived (HD-derived) peripheral blood mononuclear cells (PBMC). These results highlight the presence of antitumor CD8+ T cell surveillance against hERV3895 antigens, suggesting their clinical applications in patients with RCC.

  DOI PubMed

• Combined chemoradiotherapy and programmed cell death-ligand 1 blockade leads to changes in the circulating T-cell receptor repertoire of patients with non-small-cell lung cancer.

  Masanori Someya, Serina Tokita, Takayuki Kanaseki, Mio Kitagawa, Tomokazu Hasegawa, Takaaki Tsuchiya, Yuki Fukushima, Toshio Gocho, Yoh Kozuka, Shoh Mafune, Yutaro Ikeuchi, Mamoru Takahashi, Keigo Moniwa, Kazuhiko Matsuo, Tadashi Hasegawa, Toshihiko Torigoe, Koh-Ichi Sakata

  Cancer Science   113 ( 12 ) 4394 - 4400  2022.12  [International journal]

  Authorship：   Corresponding author

  　View Summary

  Combined chemoradiotherapy (CRT) and programmed cell death-ligand 1 (PD-L1) blockade is a new care standard for unresectable stage III non-small-cell lung cancer (NSCLC). Although this consolidation therapy has improved the overall survival of patients with NSCLC, the synergistic action mechanisms of CRT and immunotherapy on T cells remain unclear. In addition, there is a paucity of reliable biomarkers to predict clinical responses to therapy. In this study, we analyzed T-cell receptor (TCR) sequences in the peripheral blood of five patients with NSCLC. T-cell receptor analysis was undertaken before treatment, after CRT, and after PD-L1 blockade. Notably, we observed the expansion and alteration of the dominant T-cell clonotypes in all cases with a complete response. In contrast, neither expansion nor alteration of the TCR repertoire was observed in cases with progressive disease. T cell expansion was initiated after CRT and was further enhanced after PD-L1 blockade. Our findings suggest the systemic effect of CRT on circulating T cells in addition to the curative effect on limited tumor sites. Dynamic changes in circulating T-cell clonotypes could have a prognostic significance for combined CRT and PD-L1 blockade.

  DOI PubMed

• Characterization of Proteasome-Generated Spliced Peptides Detected by Mass Spectrometry.

  Koji Kato, Munehide Nakatsugawa, Serina Tokita, Yoshihiko Hirohashi, Terufumi Kubo, Tomohide Tsukahara, Kenji Murata, Hirofumi Chiba, Hiroki Takahashi, Naoto Hirano, Takayuki Kanaseki, Toshihiko Torigoe

  Journal of Immunology (Baltimore, Md. : 1950)   208 ( 12 ) 2856 - 2865  2022.05  [International journal]

  Authorship：   Corresponding author

  　View Summary

  CD8+ T cells recognize peptides displayed by HLA class I molecules and monitor intracellular peptide pools. It is known that the proteasome splices two short peptide fragments. Recent studies using mass spectrometry (MS) and bioinformatics analysis have suggested that proteasome-generated spliced peptides (PSPs) may account for a substantial proportion of HLA class I ligands. However, the authenticity of the PSPs identified using bioinformatics approaches remain ambiguous. In this study, we employed MS-based de novo sequencing to directly capture cryptic HLA ligands that were not templated in the genome. We identified two PSPs originating from the same protein in a human colorectal cancer line with microsatellite instability. Healthy donor-derived CD8+ T cells readily responded to the two PSPs, showing their natural HLA presentation and antigenicity. Experiments using minigene constructs demonstrated proteasome-dependent processing of two PSPs generated by standard and reverse cis splicing, respectively. Our results suggest a broader diversity of HLA class I Ag repertoires generated by proteasomal splicing, supporting the advantage of MS-based approaches for the comprehensive identification of PSPs.

  DOI PubMed

• HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability.

  Masahito Kawazu, Toshihide Ueno, Koichi Saeki, Nicolas Sax, Yosuke Togashi, Takayuki Kanaseki, Keigo Chida, Fumishi Kishigami, Kazuhito Sato, Shinya Kojima, Masafumi Otsuka, Akihito Kawazoe, Hitomi Nishinakamura, Maeda Yuka, Yoko Yamamoto, Kazuo Yamashita, Satoshi Inoue, Tokiyoshi Tanegashima, Daisuke Matsubara, Kenta Tane, Yosuke Tanaka, Hisae Iinuma, Yojiro Hashiguchi, Shoichi Hazama, Seik-Soon Khor, Katsushi Tokunaga, Masahiro Tsuboi, Toshiro Niki, Masatoshi Eto, Kohei Shitara, Toshihiko Torigoe, Soichiro Ishihara, Hiroyuki Aburatani, Hiroshi Haeno, Hiroyoshi Nishikawa, Hiroyuki Mano

  Gastroenterology   162 ( 3 ) 799 - 812  2022.03  [International journal]

  　View Summary

  BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

  DOI PubMed

• Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy.

  Koji Nagaoka, Changbo Sun, Yukari Kobayashi, Takayuki Kanaseki, Serina Tokita, Toshihiro Komatsu, Kazuhiro Maejima, Junichiro Futami, Sachiyo Nomura, Keiko Udaka, Hidewaki Nakagawa, Toshihiko Torigoe, Kazuhiro Kakimi

  Cancers   14 ( 1 )  2021.12  [International journal]

  　View Summary

  To develop combination immunotherapies for gastric cancers, immunologically well-characterized preclinical models are crucial. Here, we leveraged two transplantable murine gastric cancer cell lines, YTN2 and YTN16, derived from the same parental line but differing in their susceptibility to immune rejection. We established their differential sensitivity to immune checkpoint inhibitors (ICI) and identified neoantigens. Although anti-CTLA-4 mAbs eradicated YTN16 tumors in 4 of 5 mice, anti-PD-1 and anti-PD-L1 mAbs failed to eradicate YTN16 tumors. Using whole-exome and RNA sequencing, we identified two and three neoantigens in YTN2 and YTN16, respectively. MHC class I ligandome analysis detected the expression of only one of these neoantigens, mutated Cdt1, but the exact length of MHC binding peptide was determined. Dendritic cell vaccine loaded with neoepitope peptides and adoptive transfer of neoantigen-specific CD8+ T cells successfully inhibited the YTN16 tumor growth. Targeting mutated Cdt1 had better efficacy for controlling the tumor. Therefore, mutated Cdt1 was the dominant neoantigen in these tumor cells. More mCdt1 peptides were bound to MHC class I and presented on YTN2 surface than YTN16. This might be one of the reasons why YTN2 was rejected while YTN16 grew in immune-competent mice.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• プロテオゲノミクスHLAリガンドーム解析

  金関 貴幸

  腫瘍内科 ( 科学評論社 )  31 ( 3 ) 289 - 293  2023.03

• がん免疫療法を理解するための免疫学の知識

  金関 貴幸

  泌尿器care & cure uro-lo : 治療と看護みんなつながるマガジン ( メディカ出版 )  27 ( 3 ) 298 - 303  2022.06

• ネオアンチゲンの同定とワクチン応用

  金関 貴幸

  実験医学   40 ( 16 ) 2562 - 2567  2022

• プロテオゲノミクスによるネオアンチゲン・新規がん抗原同定と免疫治療

  金関 貴幸

  腫瘍内科 ( 科学評論社 )  27 ( 5 ) 558 - 562  2021.05

  CiNii

• プロテオゲノミクスによるHLA提示がん抗原解析の新展開

  金関 貴幸

  癌と化学療法   46 ( 9 )  2019.09

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Industrial Property Rights 【 display / non-display 】

Industrial Property Rights 【 display / non-display 】

• ヒト内在性レトロウイルス由来腫瘍抗原

  金関貴幸, 時田芹奈, 鳥越俊彦

  Patent

• 対象由来のネオアンチゲンを選択するための方法

  金関貴幸, 時田芹奈, 鳥越俊彦

  Patent

• 腫瘍抗原ペプチド

  特許第6960179号

  佐藤 昇志, 鳥越 俊彦, 廣橋 良彦, 金関 貴幸, コーチン ビタリー, 高谷 あかり, 後藤 正志

  Patent

  J-GLOBAL

• 腫瘍抗原ペプチド

  佐藤 昇志, 鳥越 俊彦, 廣橋 良彦, 金関 貴幸, コーチン ビタリー, 高谷 あかり, 後藤 正志

  Patent

  J-GLOBAL

• 腫瘍抗原ペプチド

  特許第7266834号

  鳥越 俊彦, 金関 貴幸, コーチン ビタリー, 菊池 泰弘

  Patent

  J-GLOBAL

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 北海道科学技術奨励賞

  2018  

• 日本病理学会学術研究賞

  2018  

Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 新しいネオ抗原検出技術による腫瘍特異的CD4+T細胞の機能解析とがん治療応用

  基盤研究(B)

  Project Year :

  2024.04

  -

  2027.03

   

  Authorship： Principal investigator

• ネオ抗原特異的T細胞の分子変化に基づく新規免疫チェックポイント分子の探索

  基盤研究(C)

  Project Year :

  2024.04

  -

  2027.03

   

  Authorship： Coinvestigator(s)

• Identification of oral cancer neoantigens with proteogenomics HLA ligandome analysis

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2023.04

  -

  2026.03

   

  Authorship： Coinvestigator(s)

• 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

  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)

  Project Year :

  2023

  -

  2024

   

  Authorship： Coinvestigator(s)

• NAPプロテオゲノミクス解析基盤によるT細胞腫瘍抗原オミクス研究

  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)

  Project Year :

  2022

  -

  2024

   

  Authorship： Principal investigator

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Presentations 【 display / non-display 】

Presentations 【 display / non-display 】

• 免疫プロテオゲノミクスによるがん抗原探索

  日本病理学会カンファレンス（シンポジウム講演） 

  Presentation date： 2023.08

  Event date：

  2023

  　

  　

• Rapid identification of immunogenic neoantigens using surrogate immunopeptidomes

  日本癌学会（特別シンポジウム講演） 

  Presentation date： 2023.09

  Event date：

  2023

  　

  　

• 臨床的に意義のあるネオアンチゲン探索

  日本がん免疫学会（シンポジウム講演） 

  Presentation date： 2022.07

  Event date：

  2022

  　

  　

• 遺伝子変異由来ネオアンチゲンの実像と患者T細胞応答

  日本臨床腫瘍学会（シンポジウム講演） 

  Presentation date： 2021.02

  Event date：

  2021

  　

  　

• プロテオゲノミクスによるHLA提示ペプチド解析と非コード領域遺伝子に由来する 新しいがん抗原クラスの同定

  日本がん免疫学会（シンポジウム講演） 

  Presentation date： 2020.10

  Event date：

  2020

  　

  　

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Committee Memberships 【 display / non-display 】

Committee Memberships 【 display / non-display 】

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    日本がん免疫学会（評議員）

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    日本癌学会（評議員）

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    日本病理学会（評議員 / 病理専門医）

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    日本臨床ストレス応答学会（評議員）