マイクロサテライト高度不安定性がんの免疫回避メカニズム解明

• Project/Area Number: 21H02772
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: 河津 正人 千葉県がんセンター(研究所), がん治療開発グループ 細胞治療開発研究部, 部長 (20401078)
• Co-Investigator(Kenkyū-buntansha): 川添 彬人 国立研究開発法人国立がん研究センター, 東病院, 医員 (20754675) ; 波江野 洋 東京理科大学, 研究推進機構生命医科学研究所, 准教授 (70706754) ; 坂下 信悟 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (40620638)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: マイクロサテライト不安定性 / 抗腫瘍免疫 / 大腸がん / 腫瘍免疫 / 免疫チェックポイント阻害剤 / ロングリードシーケンサー / 全長転写産物解析 / 大腸癌 / 転写バリアント

Outline of Research at the Start

マイクロサテライト高度不安定性（MSI-H）腫瘍に対して免疫チェックポイント阻害剤（ICI）は顕著な効果を示し臨床上の有用性が示されているが、少なくとも半数程度の症例に対しては十分な効果が得られない。MSI-H腫瘍におけるICI治療有効性と関連するゲノム異常の報告は限られている。申請者は、MSI-H腫瘍の免疫ゲノム解析を進め、腫瘍免疫状態の違いと相関するゲノム異常を複数同定した。本研究課題ではそれらのゲノム異常と腫瘍免疫の相互作用の詳細な分子メカニズムを解明し、ICIをはじめとした腫瘍免疫療法の改良・開発のための基礎的知見を得ることを目的とした解析を行う。

Outline of Annual Research Achievements

マイクロサテライト高度不安定性（MSI-H）腫瘍に対して免疫チェックポイント阻害剤（ICI）は顕著な効果を示し臨床上の有用性が示されているが、少なくとも半数程度の症例に対しては十分な効果が得られない。本研究課題ではゲノム異常に由来する転写制御異常と腫瘍免疫の相互作用の詳細な分子メカニズムを解明し、ICIをはじめとした腫瘍免疫療法の改良・開発のための基礎的知見を得ることを目的とする。
子宮体癌のおよそ20%はマイクロサテライト不安定性を示す。MSI-H大腸癌と同様にICIが有効となることが期待されているが、大腸とは異なる臓器特異性な微小環境を有し、遺伝子変異の特徴も異なり、MSI-H大腸癌とは異なる免疫応答性を示すと考えられる。本年度は高悪性度子宮体癌のゲノム異常およびmRNA発現プロファイルのデータ解析を進めた。その結果、子宮体癌においては、MSI-Hにより腫瘍特異的抗原の量が多いがんにおいて、必ずしも抗原提示機能が十分に機能していない可能性が示唆された。逆に、腫瘍特異的抗原が多くないものの、抗原提示機能が比較的高い腫瘍が存在する可能性が示唆された。これは大腸がんにおいてはMSI-Hにより腫瘍特異的抗原の量が多いがんでは、多くの場合は抗原提示機能が高いこととは対照的であり、子宮体癌と大腸癌の免疫応答性の違いの原因であると考えられた。
さらに、子宮体癌の網羅的全長転写産物解析を継続した。4症例のデータを使いして取得し、累計16症例のデータを集積した。スプライスバリアンとの違いを比較し、エピゲノム制御に関わる遺伝子およびミトコンドリで機能する遺伝子において、組織型によってスプライス制御が異なる可能性を見出した。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Deletion of Pak1 in CD11c-Positive Cells Confers Resistance to Mouse Skin Carcinogenesis (2024)
  • Author(s): Okumura Kazuhiro、Morinaga Takao、Saito Megumi、Tokunaga Yurika、Otoyama Keisuke、Tanaka Sora、Isogai Eriko、Kawazu Masahito、Togashi Yosuke、Araki Kimi、Wakabayashi Yuichi
  • Journal Title: Journal of Investigative Dermatology Volume: - Issue: 8 Pages: 1890-1893.e5
  • DOI: 10.1016/j.jid.2024.01.021
  • Peer Reviewed / Open Access
• [Journal Article] Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment (2024)
  • Author(s): Zhou W, Kawashima S, Ishino T, Kawase K, Ueda Y, Yamashita K, Watanabe T, Kawazu M, Dansako H, Suzuki Y, Nishikawa H, Inozume T, Nagasaki J, Togashi Y.
  • Journal Title: Cell Reports Volume: - Issue: 2 Pages: 113797-113797
  • DOI: 10.1016/j.celrep.2024.113797
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects (2023)
  • Author(s): Kawase K、Kawashima S、Nagasaki J、Inozume T、Tanji E、Kawazu M、Hanazawa T、Togashi Y
  • Journal Title: Cancer Immunology Research Volume: In press Issue: 7 Pages: 895-908
  • DOI: 10.1158/2326-6066.cir-22-0815
  • Peer Reviewed
• [Journal Article] Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland (2023)
  • Author(s): Kobayashi Kenya、Kawazu Masahito、Yoshimoto Seiichi、Ueno Toshihide、Omura Go、Saito Yuki、Ando Mizuo、Ryo Eigitsu、Sakyo Airi、Yoshida Akihiko、Yatabe Yasushi、Mano Hiroyuki、Mori Taisuke
  • Journal Title: Laboratory Investigation Volume: 103 Issue: 10 Pages: 100213-100213
  • DOI: 10.1016/j.labinv.2023.100213
  • Peer Reviewed
• [Journal Article] Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers (2023)
  • Author(s): Kobayashi Y, Niida A, Nagayama S, Saeki K, （中略）, Mizuno S, Kawazu M, Kohsaka S, Ueno T, Mano H, Ishihara S, Uemura M, Mori M, Doki Y, Eguchi H, Oshima M, Suzuki Y, Shibata T, Mimori K.
  • Journal Title: Br J Cancer Volume: 129 Issue: 7 Pages: 1105-1118
  • DOI: 10.1038/s41416-023-02395-8
  • Peer Reviewed / Open Access
• [Journal Article] Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors (2023)
  • Author(s): Ikeda Hideki、Nagasaki Joji、Shimizu Daiki、Katsuya Yuki、Horinouchi Hidehito、Hosomi Yukio、Tanji Etsuko、Iwata Takekazu、Itami Makiko、Kawazu Masahito、Ohe Yuichiro、Suzuki Takuji、Togashi Yosuke
  • Journal Title: JTO Clinical and Research Reports Volume: 4 Issue: 10 Pages: 100573-100573
  • DOI: 10.1016/j.jtocrr.2023.100573
  • Peer Reviewed / Open Access
• [Journal Article] Strategic Approach to Heterogeneity Analysis of Cutaneous Adnexal Carcinomas Using Computational Pathology and Genomics (2023)
  • Author(s): Nishimura Yuuki、Ryo Eijitsu、Inoue Satoshi、Kawazu Masahito、Ueno Toshihide、Namikawa Kenjiro、Takahashi Akira、Ogata Dai、Yoshida Akihiko、Yamazaki Naoya、Mano Hiroyuki、Yatabe Yasushi、Mori Taisuke
  • Journal Title: JID Innovations Volume: 3 Issue: 6 Pages: 100229-100229
  • DOI: 10.1016/j.xjidi.2023.100229
  • Peer Reviewed / Open Access
• [Journal Article] Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens (2023)
  • Author(s): Ishino Takamasa、Kawashima Shusuke、Tanji Etsuko、Ueno Toshihide、Ueda Youki、Ogasawara Sadahisa、Sato Kazuhito、Mano Hiroyuki、Ishihara Soichiro、Kato Naoya、Kawazu Masahito、Togashi Yosuke
  • Journal Title: British Journal of Cancer Volume: 128 Issue: 6 Pages: 1166-1175
  • DOI: 10.1038/s41416-023-02165-6
  • Peer Reviewed / Open Access
• [Journal Article] MSIMEP: Predicting microsatellite instability from microarray DNA methylation tumor profiles (2023)
  • Author(s): Santamarina-Garcia M, Brea-Iglesias J, Bramsen JB, Fuentes-Losada M, Caneiro-Gomez FJ, Vazquez-Bueno JA, Lazare-Iglesias H, Fernandez-Diaz N, Sanchez-Rivadulla L, Betancor YZ, Ferreiro-Pantin M, Conesa-Zamora P, Antunez-Lopez JR, Kawazu M, Esteller M, Andersen CL, Tubio JMC, Lopez-Lopez R, Ruiz-Banobre J
  • Journal Title: iScience Volume: 26 Issue: 3 Pages: 106127-106127
  • DOI: 10.1016/j.isci.2023.106127
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of organoid culture from HPV18-positive small cell carcinoma of the uterine cervix for precision medicine (2023)
  • Author(s): Kusakabe M, Taguchi A, Tanikawa M, Hoshi D, Tsuchimochi S, Qian X, Toyohara Y, Kawata A, Wagatsuma R, Yamaguchi K, Yamamoto Y, Ikemura M, Sone K, Mori-Uchino M, Matsunaga H, Tsuruga T, Nagamatsu T, Kukimoto I, Wada-Hiraike O, Kawazu M, Ushiku T, Takeyama H, Oda K, Kawana K, Hippo Y, Osuga Y.
  • Journal Title: Cancer Med Volume: 12 Issue: 7 Pages: 8476-8489
  • DOI: 10.1002/cam4.5588
  • Peer Reviewed / Open Access
• [Journal Article] MYC/glutamine dependency is a therapeutic vulnerability in pancreatic cancer with deoxycytidine kinase inactivation-induced gemcitabine resistance (2023)
  • Author(s): Dash Suman, Ueda Takeshi, Komuro Akiyoshi, Amano Hisayuki, Honda Masahiko, Kawazu Masahito, Okada Hitoshi.
  • Journal Title: Molecular Cancer Research Volume: online publication Issue: 5 Pages: 444-457
  • DOI: 10.1158/1541-7786.mcr-22-0554
  • Peer Reviewed / Open Access
• [Journal Article] Cells with stem‐like properties are associated with the development of HPV18‐positive cervical cancer (2022)
  • Author(s): Kusakabe Misako、Wada‐Hiraike Osamu(16)、Kawazu Masahito、Ushiku Tetsuo、Takeyama Haruko、Oda Katsutoshi、Kawana Kei、Mano Hiroyuki、Osuga Yutaka
  • Journal Title: Cancer Science Volume: 114 Issue: 3 Pages: 885-895
  • DOI: 10.1111/cas.15664
  • Peer Reviewed / Open Access
• [Journal Article] Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration (2022)
  • Author(s): T. Morinaga, T. Inozume, Y. Togashi et al.
  • Journal Title: Cancer Research Communications Volume: 2 Issue: 7 Pages: 739-753
  • DOI: 10.1158/2767-9764.crc-22-0050
  • Peer Reviewed / Open Access
• [Journal Article] HSP90 inhibition overcomes resistance to molecular targeted therapy in BRAFV600E mutant high-grade glioma (2022)
  • Author(s): Sasame J, Ikegaya N, Kawazu M, Natsumeda M, Hayashi T, Isoda M, Satomi K, Tomiyama A, Oshima A, Honma H, Miyake Y, Takabayashi K, Nakamura T, Ueno T, Matsushita Y, Iwashita H, Kanemaru Y, Murata H, Ryo A, Terashima K, Yamanaka S, Fujii Y, Mano H, Komori T, Ichimura K, Cahill DP, Wakimoto H, Yamamoto T, Tateishi K.
  • Journal Title: Clin Cancer Res Volume: 印刷中 Issue: 11 Pages: 2425-2439
  • DOI: 10.1158/1078-0432.ccr-21-3622
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Exploration of predictive biomarkers for postoperative recurrence of stage II/III colorectal cancer using genomic sequencing (2022)
  • Author(s): Kishigami Fumishi、Tanaka Yosuke、Yamamoto Yoko、Ueno Toshihide、Kojima Shinya、Sato Kazuhito、Inoue Satoshi、Sugaya Saori、Ishihara Soichiro、Mano Hiroyuki、Kawazu Masahito
  • Journal Title: Cancer Medicine Volume: 11 Issue: 18 Pages: 3457-3470
  • DOI: 10.1002/cam4.4710
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti?PD-1 Therapy (2022)
  • Author(s): Chida K、Kawazoe A、Suzuki T、Kawazu M、Ueno T、Takenouchi K、Nakamura Y、Kuboki Y、Kotani D、Kojima T、Bando H、Mishima S、Kuwata T、Sakamoto N、Watanabe J、Mano H、Ikeda M、Shitara K、Endo I、Nakatsura T、Yoshino T
  • Journal Title: Clinical Cancer Research Volume: 28 Issue: 10 Pages: 2110-2117
  • DOI: 10.1158/1078-0432.ccr-22-0041
  • Peer Reviewed
• [Journal Article] HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability (2022)
  • Author(s): Kawazu M, Ueno T, Saeki K, Sax N, Togashi Y, Kanaseki T, Chida K, Kishigami F, Sato K, Kojima S, Tanegashima T, Matsubara D, Tane K, Tanaka Y, Iinuma H, Hashiguchi Y, Hazama S, Khor SS, Tokunaga K, Tsuboi M, Niki T, Eto M, Shitara K, Torigoe T, Ishihara S, Aburatani H, Haeno H, Nishikawa H, Mano H
  • Journal Title: Gastroenterology Volume: 162 Issue: 3 Pages: 799-812
  • DOI: 10.1053/j.gastro.2021.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2and IDH1/2 mutations (2022)
  • Author(s): Yasuda Takahiko、Ogawa Seishi, et al.
  • Journal Title: Blood Volume: 139 Issue: 12 Pages: 1850-1862
  • DOI: 10.1182/blood.2021011921
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments (2022)
  • Author(s): Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H
  • Journal Title: Cancer Cell Volume: 40 Issue: 2 Pages: 201-218
  • DOI: 10.1016/j.ccell.2022.01.001
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes (2022)
  • Author(s): Nagasaki Joji、Inozume Takashi、Yosuke Togashi et al.
  • Journal Title: Cell Reports Volume: 38 Issue: 5 Pages: 110331-110331
  • DOI: 10.1016/j.celrep.2022.110331
  • NAID: 120007192058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer (2021)
  • Author(s): Namba Shinichi、Ueno Toshihide、Kojima Shinya、Kobayashi Kenya、Kawase Katsushige、Tanaka Yosuke、Inoue Satoshi、Kishigami Fumishi、Kawashima Shusuke、Maeda Noriko、Ogawa Tomoko、Hazama Shoichi、Togashi Yosuke、Ando Mizuo、Shiraishi Yuichi、Mano Hiroyuki、Kawazu Masahito
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 1320-1320
  • DOI: 10.1038/s42003-021-02833-4
  • Peer Reviewed / Open Access
• [Journal Article] TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment (2021)
  • Author(s): Kawashima S, Inozume T, Kawazu M, Ueno T, Nagasaki J, Tanji E, Honobe A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Kawasaki T, Kiniwa Y, Yamasaki O, Fukushima S, Ikehara Y, Mano H, Suzuki Y, Nishikawa H, Matsue H, Togashi Y.
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 9 Issue: 11 Pages: e003134-e003134
  • DOI: 10.1136/jitc-2021-003134
  • NAID: 120007175403
  • Peer Reviewed / Open Access
• [Journal Article] Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities (2021)
  • Author(s): Tanaka Yosuke、Chiwaki Fumiko、Kojima Shinya、Kawazu Masahito、Komatsu Masayuki、Ueno Toshihide、Inoue Satoshi、Sekine Shigeki、Matsusaki Keisuke、Matsushita Hiromichi、Boku Narikazu、Kanai Yae、Yatabe Yasushi、Sasaki Hiroki、Mano Hiroyuki
  • Journal Title: Nature Cancer Volume: 2 Issue: 9 Pages: 962-977
  • DOI: 10.1038/s43018-021-00240-6
  • Peer Reviewed / Open Access
• [Journal Article] A Low Tumor Mutational Burden and <i>PTEN</i> Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors (2021)
  • Author(s): Chida Keigo, Kawazoe Akihito, Kawazu Masahito et al.
  • Journal Title: Clinical Cancer Research Volume: 27 Issue: 13 Pages: 3714-3724
  • DOI: 10.1158/1078-0432.ccr-21-0401
  • NAID: 130008144997
  • Peer Reviewed / Open Access
• [Journal Article] KDM4B promotes acute myeloid leukemia associated with AML1‐ETO by regulating chromatin accessibility (2021)
  • Author(s): Ueda Takeshi、Kanai Akinori、Komuro Akiyoshi、Amano Hisayuki、Ota Kazushige、Honda Masahiko、Kawazu Masahito、Okada Hitoshi
  • Journal Title: FASEB BioAdvances Volume: 3 Issue: 12 Pages: 1020-1033
  • DOI: 10.1096/fba.2021-00030
  • Peer Reviewed / Open Access
• [Journal Article] Highly sensitive fusion detection using plasma cell-free RNA in non-small-cell lung cancers. (2021)
  • Author(s): Hasegawa N, Kohsaka S, Kurokawa K, Shinno Y, Takeda Nakamura I, Ueno T, Kojima S, Kawazu M, Suehara Y, Ishijima M, Goto Y, Kojima Y, Yonemori K, Hayashi T, Saito T, Shukuya T, Takahashi F, Takahashi K, Mano H.
  • Journal Title: Cancer Sci Volume: 112 Issue: 10 Pages: 4393-4403
  • DOI: 10.1111/cas.15084
  • Peer Reviewed / Open Access
• [Journal Article] Development of an optimal protocol for molecular profiling of tumor cells in pleural effusions at single-cell level (2021)
  • Author(s): Takeda Nakamura I, Ikegami M, Hasegawa N, Hayashi T, Ueno T, Kawazu M, Yagishita S, Goto Y, Shinno Y, Kojima Y, Takamochi K, Takahashi F, Takahashi K, Mano H, Kohsaka S
  • Journal Title: Cancer Sci Volume: － Issue: 5 Pages: 2006-2019
  • DOI: 10.1111/cas.14821
  • Peer Reviewed / Open Access
• [Presentation] High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects (2023)
  • Author(s): Kawase K, Kawashima S, Nagasaki J, Inozume T, Yamamoto H, Kawazu M, Hanazawa T, Togashi Y
  • Organizer: AACR annual meeting 2023
  • Int'l Joint Research
• [Presentation] ロングリードシーケンサーを用いたがん関連転写バリアントの探索 (2023)
  • Author(s): 河津 正人、盛永 敬郎、リン ジェイソン
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] マイクロサテライト不安定性大腸癌における抗原提示機能障害 (2022)
  • Author(s): 河津正人
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] 乳癌におけるTNS3バリアント発現差の同定と解析 (2022)
  • Author(s): 盛永 敬郎、リン ジェイソン、河津 正人
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] High Resolution HLA Typing allows insight into Immune Evasion in Colon Cancer (2022)
  • Author(s): 河津正人
  • Organizer: PacBio Asia Pacific Webinar Series
  • Invited
• [Presentation] マイクロサテライト不安定性大腸がんの抗原提示機能障害の評価方法 (2021)
  • Author(s): 河津正人
  • Organizer: 第34回日本バイオセラピィ学会学術集会総会
  • Invited
• [Presentation] Full-length Transcriptome Analysis of Breast Cancer with Iso-Seq (2021)
  • Author(s): 河津正人
  • Organizer: PacBio Virtual User Meeting
  • Invited
• [Book] 第１章－２ 染色体・ゲノム異常、日本臨床腫瘍学会（編）新臨床腫瘍学（改訂第7版） (2024)
  • Author(s): 河津正人
  • Total Pages: 8
  • Publisher: 南江堂
  • ISBN: 9784524204267
• [Book] 第３章-４ がん細胞からみた免疫応答とゲノミクス、もっとよくわかる！腫瘍免疫学 (2023)
  • Author(s): 西川 博嘉（編）
  • Total Pages: 8
  • Publisher: 羊土社
  • ISBN: 4758122121
• [Book] 第４章-４ ゲノムからみたがん免疫プレシジョン医療、もっとよくわかる！腫瘍免疫学 (2023)
  • Author(s): 西川 博嘉（編）
  • Total Pages: 12
  • Publisher: 羊土社
  • ISBN: 4758122121