免疫チェックポイント分子HLA-Fを標的とした新規がん免疫療法の開発

• Project/Area Number: 21K07246
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Nara Medical University
• Principal Investigator: 王寺 典子 (下嶋典子) 奈良県立医科大学, 医学部, 助教 (30398432)
• Co-Investigator(Kenkyū-buntansha): 伊藤 利洋 奈良県立医科大学, 医学部, 教授 (00595712)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HLA-F / antibody / immunotherapy / PDX / SCID / SCID-beige / tumor / 抗体療法 / 免疫療法 / HLA class Ib

Outline of Research at the Start

免疫チェックポイント阻害薬を始めとする免疫療法は、一定の効果はあるが、全てのがん、全ての患者にいまだ適用できておらず、新たな標的分子の探索は必須である。
申請者は、HLA-Fが悪性腫瘍に高発現することをすでに見出しており、また、抑制性のNKレセプターと会合し、細胞傷害活性を抑制することからHLA-Fも免疫チェックポイント分子と同様に腫瘍免疫抑制に寄与しているのではないかと考えた。すでに、大腸癌臨床検体で、HLA-FのブロッキングによりTリンパ球のIFN-γ産生増強を確認しており、本研究では、このHLA-Fブロッキングによる抗腫瘍効果の作用機序を検証する。

Outline of Annual Research Achievements

ヒト白血球抗原（Human leukocyte antigen、HLA）-Fは多型性に乏しいHLA クラスIb分子の一つで、抑制性のkiller cell Immunoglobulin like receptor (KIR)と会合し、NK細胞、T細胞の細胞傷害活性を抑制する。我々は、HLA-Fが低分化・未分化癌に高発現することをすでに見出しており、悪性腫瘍に高発現するHLA-Fを抗HLA-F抗体でブロックすることにより、抑制性KIRを介して抑制されたNK細胞・T細胞を再活性化する新規がん免疫療法が可能ではないかと考え本研究を開始した。
これまでに大腸癌組織より患者由来大腸癌細胞を分離継代し、これをSCIDマウスおよびSCID-beigeマウスで順化し、マウスモデルに使用可能な患者由来大腸癌細胞を作製した。これを、SCIDマウスおよびSCID-beigeマウスに移入して患者由来大腸癌モデルマウスを作製し、抗HLA-F抗体投与による腫瘍縮小効果を検証したところ、SCID-beigeマウスでは、抗HLA-F抗体投与による腫瘍縮小効果は見られなかったが、SCIDマウスにおいて、腫瘍増殖率の低下傾向が見られた。この縮小効果が、マウスNK細胞の機能するSCIDマウスにおいて見られたことから、NK細胞と抗HLA-F抗体の抗体依存性細胞傷害活性による腫瘍増殖抑制によると考え、今年度は、SCID-beigeマウスに患者由来大腸癌細胞を接種し、腫瘍形成後、抗HLA-F抗体とヒトNK細胞を腫瘍部位に接種し、腫瘍縮小効果を検証した。昨年度同様、抗HLA-F抗体投与による腫瘍縮小効果は認められたが、患者由来大腸癌SCID-beigeマウスモデルにおいて、ヒトNK細胞と抗HLA-F抗体投与による腫瘍縮小効果は認められなかった。今後、抗HLA-F抗体投与によるNK細胞の再活性化については、in vitroの解析を中心に検討予定である。

Research Products

• [Journal Article] CD8+ T-cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance (2024)
  • Author(s): H, Aoki., M, Kitabatake., H, Abe., P, Xu., M, Tsunoda., S, Shichino., A, Hara., N, Ouji- Sageshima., C, Motozono., T, Ito., K, Matsushima., and S, Ueha
  • Journal Title: Cell reports Volume: 43 Issue: 3 Pages: 113887-113902
  • DOI: 10.1016/j.celrep.2024.113887
  • Peer Reviewed / Open Access
• [Journal Article] Transition of Antibody Titers after SARS-CoV-2 mRNA Vaccination in Japanese Healthcare Workers (2023)
  • Author(s): Kitabatake Masahiro、Ouji-Sageshima Noriko、Sonobe Shota、Furukawa Ryutaro、Konda Makiko、Hara Atsushi、Aoki Hiroyasu、Suzuki Yuki、Imakita Natsuko、Nakano Akiyo、Fujita Yukio、Shichino Shigeyuki、Nakano Ryuichi、Ueha Satoshi、Kasahara Kei、Muro Shigeo、Yano Hisakazu、Matsushima Kouji、Ito Toshihiro
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 76 Issue: 1 Pages: 72-76
  • DOI: 10.7883/yoken.JJID.2022.041
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2023-01-31
  • Peer Reviewed / Open Access
• [Journal Article] A Disintegrin and Metalloproteinase with Thrombospondin Motifs 4 Regulates Pulmonary Vascular Hyperpermeability through Destruction of Glycocalyx in Acute Respiratory Distress Syndrome (2023)
  • Author(s): Konda Makiko、Kitabatake Masahiro、Ouji-Sageshima Noriko、Tonomura Rei、Furukawa Ryutaro、Sonobe Shota、Terada-Ikeda Chiyoko、Takeda Maiko、Kawaguchi Masahiko、Ito Toshihiro
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 22 Pages: 16230-16230
  • DOI: 10.3390/ijms242216230
  • Peer Reviewed / Open Access
• [Journal Article] Antiviral Effect of Candies Containing Persimmon-Derived Tannin against SARS-CoV-2 Delta Strain (2023)
  • Author(s): Furukawa Ryutaro、Kitabatake Masahiro、Ouji-Sageshima Noriko、Tomita Dai、Kumamoto Makiko、Suzuki Yuki、Nakano Akiyo、Nakano Ryuichi、Matsumura Yoko、Kayano Shin-ichi、Yano Hisakazu、Tamaki Shinji、Ito Toshihiro
  • Journal Title: Viruses Volume: 15 Issue: 8 Pages: 1636-1636
  • DOI: 10.3390/v15081636
  • Peer Reviewed / Open Access
• [Journal Article] The spleen is the major site for the development and expansion of inhibitor producing-cells in hemophilia A mice upon FVIII infusion developing high-titer inhibitor (2023)
  • Author(s): Akihisa Oda, Shoko Furukawa, Masahiro Kitabatake, Noriko Ouji-Sageshima, Shota Sonobe, Kaoru Horiuchi, Yuto Nakajima, Kenichi Ogiwara, Ryo Goitsuka, Midori Shima, Toshihiro Ito, Keiji Nogami
  • Journal Title: Thrombosis research Volume: 3848 Pages: 00077-4
  • DOI: 10.1016/j.thromres.2023.03.003
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide from Yoshino cedar trees (Cryptomeria japonica) induces high levels of human macrophage polarization (2022)
  • Author(s): Noriko Ouji-Sageshima, Masahiro Kitabatake, Satoki Fushimi, Satoshi Suzuki, Yuzu Fukui, Ryutaro Furukawa and Toshihiro Ito
  • Journal Title: Journal of Wood Science Volume: 68 Pages: 63-63
  • Peer Reviewed
• [Journal Article] Pure Solid Pattern of Non-Small Cell Lung Cancer and Clustered Circulating Tumor Cells (2022)
  • Author(s): Sawabata Noriyoshi、Kawaguchi Takeshi、Watanabe Takashi、Yohikawa Daiki、Ouji-Sageshima Noriko、Ito Toshihiro
  • Journal Title: Cancers Volume: 14 Issue: 18 Pages: 4514-4514
  • DOI: 10.3390/cancers14184514
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persimmon-derived tannin has antiviral effects and reduces the severity of infection and transmission of SARS-CoV-2 in a Syrian hamster model (2021)
  • Author(s): Furukawa Ryutaro、Kitabatake Masahiro、Ouji-Sageshima Noriko、Suzuki Yuki、Nakano Akiyo、Matsumura Yoko、Nakano Ryuichi、Kasahara Kei、Kubo Kaoru、Kayano Shin-ichi、Yano Hisakazu、Ito Toshihiro
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 23695-23695
  • DOI: 10.1038/s41598-021-03149-3
  • Peer Reviewed / Open Access
• [Journal Article] Persimmon-derived tannin ameliorates the pathogenesis of ulcerative colitis in a murine model through inhibition of the inflammatory response and alteration of microbiota (2021)
  • Author(s): Kitabatake Masahiro、Matsumura Yoko、Ouji-Sageshima Noriko、Nishioka Tatsuki、Hara Atsushi、Kayano Shin-ichi、Ito Toshihiro
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 7286-7286
  • DOI: 10.1038/s41598-021-86608-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transition of antibody titers after the SARS-CoV-2 mRNA vaccine in Japanese healthcare workers (2021)
  • Author(s): Kitabatake Masahiro、Ouji-Sageshima Noriko、Sonobe Shota、Furukawa Ryutaro、Konda Makiko、Hara Atsushi、Aoki Hiroyasu、Suzuki Yuki、Imakita Natsuko、Nakano Akiyo、Fujita Yukio、Shichino Shigeyuki、Nakano Ryuichi、Ueha Satoshi、Kasahara Kei、Muro Shigeo、Yano Hisakazu、Matsushima Kouji、Ito Toshihiro
  • Journal Title: medRxiv Volume: - Pages: 1-9
  • DOI: 10.1101/2021.12.28.21268435
  • Open Access
• [Journal Article] Vein-first Lobectomy for Lung Cancer Assessed According to the Status of Clustered Circulating Tumour Cells (2021)
  • Author(s): SAWABATA NORIYOSHI、NAKANE SHIGERU、YOSHIKAWA DAIKI、WATANABE TAKASHI、KAWAGUCHI TAKESHI、OUJI-SAGESHIMA NORIKO、KUSHIBE KEIJI、ITO TOSHIHIRO
  • Journal Title: Cancer Diagnosis & Prognosis Volume: 1 Issue: 5 Pages: 443-450
  • DOI: 10.21873/cdp.10059
  • Peer Reviewed / Open Access
• [Journal Article] Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal-Epithelial Transition. (2021)
  • Author(s): Fujioka N, Kitabatake M, Ouji-Sageshima N, Ibaraki T, Kumamoto M, Fujita Y, Hontsu S, Yamauchi M, Yoshikawa M, Muro S, Ito T.
  • Journal Title: Int J Chron Obstruct Pulmon Dis Volume: 8 Pages: 2783-2793
  • DOI: 10.2147/copd.s324952
  • Peer Reviewed / Open Access
• [Presentation] 腫瘍細胞に発現するHLA-F分子を標的とした新規免疫療法の開発 (2023)
  • Author(s): 王寺（下嶋）典子、石谷昭子、Daniel E Geraghty、北畠正大、古川龍太郎、伊藤利洋
  • Organizer: 第31回日本組織適合性学会大会
• [Presentation] HLA-F blockade restored the cytotoxicity of NK cells against colorectal cancer. (2023)
  • Author(s): Noriko Ouji-sageshima, Masahiro Kitabatake, Ryutaro Furukawa, Toshihiro Ito
  • Organizer: 第53回日本免疫学会学術集会
• [Presentation] Antitumor effect of anti-HLA-F antibody on colon cancer in patient-derived xenografts (PDX) model. (2022)
  • Author(s): Noriko Ouji-sageshima, Masahiro Kitabatake, Ryutaro Furukawa, Toshihiro Ito
  • Organizer: 第51回日本免疫学会学術集会（The 51th Annual Meeting of the Japanese Society for Immunology）
• [Presentation] HLA-F as a new target molecule for cancer immunotherapy of colon cancer (2021)
  • Author(s): Noriko Ouji-sageshima, Masahiro Kitabatake, Ryutaro Furukawa, Toshihiro Ito
  • Organizer: 第50回日本免疫学会学術集会（The 50th Annual Meeting of the Japanese Society for Immunology）
• [Presentation] Angiopoietin like 4 plays a critical role in the development of pulmonary fibrosis (2021)
  • Author(s): Masahiro Kitabatake, Shoichiro Saito, Noriko Ouji-Sageshima, Akihisa Oda, Atsushi Hara, Tatsuro Ogawa, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Toshihiro Ito
  • Organizer: 第50回日本免疫学会学術集会（The 50th Annual Meeting of the Japanese Society for Immunology）
• [Presentation] Persimmon-derived tannin has antiviral effects in a Syrian hamster model of SARS-CoV-2 infection. (2021)
  • Author(s): Ryutaro Furukawa, Noriko Ouji Sageshima, Masahiro Kitabatake, Toshihiro Ito
  • Organizer: 第50回日本免疫学会学術集会（The 50th Annual Meeting of the Japanese Society for Immunology）
• [Presentation] Histone modification enzyme SET domain bifurcated 2 (Setdb2) contributes to the pathogenesis of acute respiratory distress syndrome (ARDS) in murine model (2021)
  • Author(s): Shota Sonobe, Masahiro Kitabatake, Atsushi Hara, Makiko Konda, Ryutaro Furukawa, Tomoko Nishimura, Noriko Ouji-Sagaeshima, Shiki Takamura, Toshihiro Ito
  • Organizer: 第50回日本免疫学会学術集会（The 50th Annual Meeting of the Japanese Society for Immunology）