Elucidation of a novel control mechanism of regulatory T cells in human head and neck squamous cell carcinoma

• Project/Area Number: 20K09911
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Nagoya City University
• Principal Investigator: Imai Masaki 名古屋市立大学, 医薬学総合研究院(医学), 講師 (30440936)
• Co-Investigator(Kenkyū-buntansha): 志馬 寛明 名古屋市立大学, 医薬学総合研究院(医学), 講師 (70372133)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); 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); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 補体 / 口腔癌

Outline of Research at the Start

癌微小環境で生じた補体系タンパクのC3aやC5aが、C3aRおよびC5aRを介してTregを誘導し、抗腫瘍免疫を抑制することが、マウスモデルで明らかにされたが、Tregに対してC3aRおよびC5aRがどのように作用するかは明らかになっていない。それ故本研究では、ヒト口腔癌において、C3aRおよびC5aRがどのようにTregを活性化し、抗腫瘍免疫を抑制しているのかを明らかにする。

Outline of Final Research Achievements

Recent studies demonstrate that the complement receptor C5aR suppresses antitumor immunity via FOXP3+ regulatory T cells (Tregs). However, the role of C5aR to activate Tregs in the tumor microenvironment is in general poorly understood. We evaluated the cell specific expression of C5aR in human head and neck squamous cell carcinoma (HNSCC) and non-cancer control. Tregs in HNSCC did not express C5aR. However, C5AR1 highly expressed in the monocyte/dendritic cell (DC) cluster of tumor-infiltrated lymphocytes (TILs) in HNSCC but not in the Treg. These data indicate C5aR indirectly activate Tregs, but not directly.

Academic Significance and Societal Importance of the Research Achievements

抗腫瘍免疫応答の抑制に中心的な働きを担うTregに対してC5aRがどのように作用するかは未だに明らかでない。また、これらの報告はマウスモデルのみで、ヒトの腫瘍浸潤リンパ球を用いたC5aRの検討は皆無であり、それをヒトで明らかにした意義は大きいと考える。さらなる研究は必要だが、本研究により、C5aRの阻害剤は新たな癌治療薬となる可能性が示された。その上、免疫チェックポイント阻害剤とは作用点が異なるため、併用することで相乗効果が期待できる。さらに、口腔癌のみならず、口腔癌以外の難治癌にも応用の可能性があり、次世代の新しい癌治療薬として期待される。

Research Products

• [Journal Article] Mature dendritic cells enriched in regulatory molecules may control regulatory T cells and the prognosis of head and neck cancer (2023)
  • Author(s): Minohara K, Imai M, Matoba T, Wing JB, Shime H, Odanaka M, Uraki R, Kawakita D, Toyama T, Takahashi S, Morita A, Murakami S, Ohkura N, Sakaguchi S, Iwasaki S, Yamazaki S.
  • Journal Title: Cancer Sci. Volume: 114 Issue: 4 Pages: 1256-1269
  • DOI: 10.1111/cas.15698
  • Peer Reviewed / Open Access
• [Journal Article] Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells. (2022)
  • Author(s): Kobayashi K, Ozeki T. Kim H, Imai M, Kojima H, Iguchi D, Fukui S, Suzuki M, Suzuki Y, Maruyama S, Ito Y, Mizuno M.
  • Journal Title: Front Med. Volume: 9 Pages: 972592-972592
  • DOI: 10.3389/fmed.2022.972592
  • Peer Reviewed / Open Access
• [Journal Article] Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens (2021)
  • Author(s): Uraki Ryuta、Imai Masaki、Ito Mutsumi、Shime Hiroaki、Odanaka Mizuyu、Okuda Moe、Kawaoka Yoshihiro、Yamazaki Sayuri
  • Journal Title: PLOS Pathogens Volume: 17 Issue: 12 Pages: e1010085-e1010085
  • DOI: 10.1371/journal.ppat.1010085
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of a Crry/p65 is reduced in acute lung injury induced by extracellular histones (2021)
  • Author(s): Nagano Fumihiko、Mizuno Tomohiro、Imai Masaki、Takahashi Kazuo、Tsuboi Naotake、Maruyama Shoichi、Mizuno Masashi
  • Journal Title: FEBS Open Bio Volume: 12 Issue: 1 Pages: 192-202
  • DOI: 10.1002/2211-5463.13322
  • Peer Reviewed / Open Access
• [Journal Article] Reply to Slominski et al.: UVB irradiation induces proenkephalin+ regulatory T cells with a wound-healing function (2021)
  • Author(s): Shime Hiroaki、Odanaka Mizuyu、Tsuiji Makoto、Matoba Takuma、Imai Masaki、Yasumizu Yoshiaki、Uraki Ryuta、Minohara Kiyoshi、Watanabe Maiko、Bonito Anthony John、Fukuyama Hidehiro、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi、Yamazaki Sayuri
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 3
  • DOI: 10.1073/pnas.2021919118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proenkephalin+regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function (2020)
  • Author(s): Shime Hiroaki、Odanaka Mizuyu、Tsuiji Makoto、Matoba Takuma、Imai Masaki、Yasumizu Yoshiaki、Uraki Ryuta、Minohara Kiyoshi、Watanabe Maiko、Bonito Anthony John、Fukuyama Hidehiro、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi、Yamazaki Sayuri
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 34 Pages: 20696-20705
  • DOI: 10.1073/pnas.2000372117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 頭頸部癌に特徴的な細胞表面CTLA-4発現制御性T細胞の遺伝子発現解析 (2022)
  • Author(s): 今井 優樹、的場 拓磨、大倉 永也、川北 大介、伊地知 圭、遠山 竜也、森田 明理、村上 信五、坂口 志文、山崎 小百合
  • Organizer: NGS EXPO 2022
• [Presentation] The complement receptor C5aR may control regulatory T cells via activation of dendritic cell in head and neck squamous cell carcinoma (2022)
  • Author(s): Masaki Imai, Sayuri Yamazaki
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] The role of regulatory T cells and dendritic cells in controlling the tumor microenvironment of human head and neck squamous cell carcinoma (2022)
  • Author(s): Kiyoshi Minohara, Masaki Imai, Takuma Matoba, James Badger Wing, Hiroaki Shime, Mizuyu Odanaka, Ryuta Uraki, Akimichi Morita, Naganari Ohkura, Shimon Sakaguchi, Sayuri Yamazaki
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] シングルセルRNAシークエンスデータを用いたヒト腫瘍微小環境下の補体活性化及び制御メカニズムの解析 (2021)
  • Author(s): 今井優樹、山崎小百合
  • Organizer: 第57回日本補体学会学術集会
• [Presentation] 制御性T細胞を標的としたSARS-CoV-2に対する新規予防法の開発 (2021)
  • Author(s): 浦木隆太、今井優樹、伊藤睦美、河岡義裕、山崎小百合
  • Organizer: 第68回日本ウイルス学会学術集会
• [Presentation] Skin regulatory T cells expanded by ultraviolet B exposure have a unique gene expression profile compared to other tissue Treg cells. (2021)
  • Author(s): Odanaka M, Shime H, Tsuiji M, Matoba T, Imai M, Yasumizu Y, Uraki R, Minohara K, Watanabe M, Bonito AJ, Fukuyama H, Ohkura N, Sakaguchi S, Morita A, Yamazaki S
  • Organizer: 第50回日本免疫学会総会・学術集会
• [Presentation] Proenkephalin+ regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function. (2021)
  • Author(s): Shime H, Odanaka M, Tsuiji M, Matoba T, Imai M, Yasumizu Y, Uraki R, Minohara K, Watanabe M, Bonito AJ, Fukuyama H, Ohkura N, Sakaguchi S, Morita A, Yamazaki S
  • Organizer: 第50回日本免疫学会総会・学術集会
• [Presentation] Transient depletion of Treg cells induces adaptive immunity to SARS-CoV-2 antigens. (2021)
  • Author(s): Uraki R, Imai M, Shime H, Kawaoka Y, Yamazaki S
  • Organizer: 第50回日本免疫学会総会・学術集会
• [Presentation] Skin regulatory T cells possessing a healing function are expanded by ultraviolet-B exposure (2020)
  • Author(s): Yamazaki S, Shime H, Odanaka M, Tsuiji M, Matoba T, Imai M, Yasumizu Y, Uraki R, Minohara K, Watanabe M, Bonito A, Fukuyama H, Ohkura N, Sakaguchi S, Morita A
  • Organizer: The 45 th Annual Meeting of the Japanese Society for Investigative Dermatology