担癌宿主における単球の動態制御

• Project/Area Number: 15F15113
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 外国
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: 松島 綱治 東京大学, 大学院医学系研究科(医学部), 教授 (50222427)
• Co-Investigator(Kenkyū-buntansha): SHAND FRANCIS 東京大学, 医学(系)研究科(研究院), 外国人特別研究員
• Project Period (FY): 2015-11-09 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,300,000 (Direct Cost: ¥2,300,000); Fiscal Year 2017: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2016: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2015: ¥700,000 (Direct Cost: ¥700,000)
• Keywords: マクロファージ / 単球 / 樹状細胞 / がん / 腫瘍免疫 / 造血

Outline of Annual Research Achievements

従来、腫瘍排除には腫瘍特異的なCD4+ T細胞とCD8+ T細胞の協働が必要と考えられてきた。一方、Foxp3+ CD4+ 制御性T細胞(Treg)は担がん宿主における免疫抑制の主役であり、多くのマウスモデルにおいて除去活性を有する抗CD4抗体の投与が強力な抗腫瘍効果をもたらすことが報告されている。我々はこれまでに、様々なマウス皮下腫瘍モデルを用いて抗CD4抗体による抗腫瘍効果の細胞・分子機序を解析し、抗CD4抗体が“CD4 help to CD8”の概念を覆す新たながん治療薬になりうるかを検討してきた。H29年度は坑CD4抗体投与による免疫賦活化作用について、特に樹状細胞の動態を中心に解析した。担がんマウスに抗CD4抗体を投与すると、CTLA-4を高発現するTregが除去されるとともに遊走性樹状細胞（mDC）における共刺激分子CD80/CD86の発現が亢進し、腫瘍所属リンパ節では腫瘍特異的CD8+ T細胞の増殖応答が亢進することが明らかになった。また、腫瘍と腫瘍所属リンパ節において共通のTCR配列を持つCD8+ T細胞クローン（臓器間重複クローン）の数、多様性ならびに各臓器中の頻度の総和が有意に増加していた。これらの結果は、抗CD4抗体投与がTregによる樹状細胞の共刺激分子発現抑制を解除することで、多様性を備えた腫瘍反応性CD8+ T細胞が大量に動員され、抗腫瘍効果に寄与することを示唆している。抗CD4抗体は免疫療法の課題であるCD4+ T細胞依存的な免疫毒性を抑制することも期待できることから、現在固形がんに対する新たな治療薬として第1相治験を進めている。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Reduction of Proliferating Olfactory Cells and Low Expression of Extracellular Matrix Genes Are Hallmarks of the Aged Olfactory Mucosa. (2018)
  • Author(s): Ueha R, Shichino S, Ueha S, Kondo K, Kikuta S, Nishijima H, Matsushima K, Yamasoba T.
  • Journal Title: Front Aging Neurosci Volume: 10 Pages: 86-86
  • DOI: 10.3389/fnagi.2018.00086
  • Peer Reviewed / Open Access
• [Journal Article] Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen. (2018)
  • Author(s): Ueta H, Kitazawa Y, Sawanobori Y, Ueno T, Ueha S, Matsushima K, Matsuno K.
  • Journal Title: Int Immunol Volume: 30 Issue: 2 Pages: 53-67
  • DOI: 10.1093/intimm/dxx078
  • Peer Reviewed / Open Access
• [Journal Article] Increased diversity with reduced "diversity evenness" of tumor infiltrating T-cells for the successful cancer immunotherapy. (2018)
  • Author(s): Hosoi A, Takeda K, Nagaoka K, Iino T, Matsushita H, Ueha S, Aoki S, Matsushima K, Kubo M, Morikawa T, Kitaura K, Suzuki R, Kakimi K.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 1058-1058
  • DOI: 10.1038/s41598-018-19548-y
  • Peer Reviewed / Open Access
• [Journal Article] The HIV co-receptor CCR5 regulates osteoclast function. (2017)
  • Author(s): Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 2226-2226
  • DOI: 10.1038/s41467-017-02368-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice. (2017)
  • Author(s): Kosugi-Kanaya M, Ueha S, Abe J, Shichino S, Shand FHW, Morikawa T, Kurachi M, Shono Y, Sudo N, Yamashita A, Suenaga F, Yokoyama A, Yong W, Imamura M, Teshima T, Matsushima K.
  • Journal Title: Front Immunol Volume: 8 Pages: 1842-1842
  • DOI: 10.3389/fimmu.2017.01842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of anti-CD4 antibody treatment and donor lymphocyte infusion ameliorates graft-versus-host disease while preserving graft-versus-tumor effects in murine allogeneic hematopoietic stem cell transplantation. (2017)
  • Author(s): Ueha S, Yokochi S, Ishiwata Y, Kosugi-Kanaya M, Shono Y, Shibayama S, Ito S, Matsushima K.
  • Journal Title: Cancer Sci Volume: 108 Issue: 10 Pages: 1967-1973
  • DOI: 10.1111/cas.13346
  • Peer Reviewed / Open Access
• [Journal Article] A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response. (2016)
  • Author(s): Ikebuchi R, Teraguchi S, Vandenbon A, Honda T, Shand FH, Nakanishi Y, Watanabe T, Tomura M.
  • Journal Title: Sci Rep. 6: 35002, doi: Volume: 6 Issue: 1 Pages: 35002-35002
  • DOI: 10.1038/srep35002
  • NAID: 120006223629
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Laryngeal mucus hypersecretion is exacerbated after smoking cessation and ameliorated by glucocorticoid administration (2016)
  • Author(s): Ueha R, Ueha S, Kondo K, Nito T, Fujimaki Y, Nishijima H, Tsunoda K, Shand FH, Matsushima K, Yamasoba T.
  • Journal Title: Toxicol Lett. Volume: 265 Pages: 140-146
  • DOI: 10.1016/j.toxlet.2016.11.023
  • Peer Reviewed / Open Access
• [Journal Article] Reduced supply of monocyte-derived macrophages leads to a transition from nodular to diffuse lesions and tissue cell activation in silica-induced pulmonary fibrosis in mice. (2015)
  • Author(s): Shigeyuki Shichino, Jun Abe, Satoshi Ueha, Mikiya Otsuji, Tatsuya Tsukui, Mizuha Kosugi-Kanaya, Francis HW Shand, Shin-ichi Hashimoto, Hiroshi I. Suzuki, Teppei Morikawa, Yutaka Inagaki, and Kouji Matsushima:
  • Journal Title: Am J Pathol Volume: 185 Issue: 11 Pages: 2923-2938
  • DOI: 10.1016/j.ajpath.2015.07.013
  • Peer Reviewed / Int'l Joint Research
• [Presentation] An anti-CD4 depleting antibody reverses regulatory T cell-induced suppression of dendritic cells while preventing non-specific CD4+ T cell responses in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: 36th Sapporo International_Cancer Symposium
  • Int'l Joint Research
• [Presentation] An anti-CD4 depleting antibody reverses regulatory T cell-induced suppression of dendritic cells while preventing non-specific CD4+ T cell responses in tumor-bearing mice (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shoji Yokochi, Yoshiro Ishiwata, Francis Shand, Shohei Hori, Kazuhiro Kakimi, Satoru Ito, Kouji Matsushima
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Identification of a functional and transcriptional signature for tumor-infiltrating dendritic cells in mouse (2017)
  • Author(s): Satoshi Ueha, Haru Ogiwara, Shigeyuki Shichino, Jun Abe, Francis Shand, Shinichi Hashimoto, Kouji Matsushima
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] The origins and development of tumor-infiltrating monocytes and macrophages (2017)
  • Author(s): Francis HW SHAND, Satoshi UEHA, Mikiya OTSUJI, Suang Suang KOID, Kouji MATSUSHIMA
  • Organizer: The 19th Takeda Science Foundation on Bioscience: Chronic Inflammation - Initiation, Progression and Resolution
  • Place of Presentation: 武田薬品研修所（大阪府吹田市）
• [Presentation] The origins and development of tumor-infiltrating monocytes and macrophages (2017)
  • Author(s): Francis HW SHAND, Satoshi UEHA, Mikiya OTSUJI, Suang Suang KOID, Kouji MATSUSHIMA
  • Organizer: The 6th NIF Winter School on Advanced Immunology
  • Place of Presentation: Singapore (Singapore)
  • Int'l Joint Research
• [Book] マクロファージの全て (2016)
  • Author(s): Shand FHW
  • Total Pages: 268
  • Publisher: 医学のあゆみ
• [Remarks] 東京大学大学院医学系研究科分子予防医学教室ホームページ
  • URL: http://www.prevent.m.u-tokyo.ac.jp/