Basic research for development of novel cancer immunotherapy based on improvement of the cancer immunosuppressive microenvironment

• Project/Area Number: 18K07277
• 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: Aichi Medical University
• Principal Investigator: Suzuki Susumu 愛知医科大学, 公私立大学の部局等, 准教授 (70518422)
• Co-Investigator(Kenkyū-buntansha): 小川 徹也 愛知医科大学, 医学部, 教授 (40334940) ; 花村 一朗 愛知医科大学, 医学部, 教授 (70440740) ; 佐野 塁 愛知医科大学, 医学部, 講師 (50813846)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 制御性T細胞 / 免疫チェックポイント阻害剤 / オプジーボ / キイトルーダ / がん免疫治療 / がん複合免疫療法 / 免疫チェックポイント / がん複合免疫治療 / 免疫抑制環境 / 頭頸部扁平上皮がん / FOXP3 / PD-1 / 免疫療法 / がん微小環境 / 免疫抑制 / 免疫治療 / CCR4 / フローサイトメトリー / 多重免疫染色 / 細胞傷害性T細胞 / バイオマーカー

Outline of Final Research Achievements

Lymphocytes called regulatory T cells (Tregs), have a suppressive effect on immunity and protect the body from excessive inflammation and autoimmune reactions. However, if the function of Treg becomes too strong, it suppresses cancer immunity and cause the onset and progression of cancer. In this study, we investigated the involvement of Tregs in cancer immunosuppression in cancer tissues for head and neck cancer, and we revealed Tregs are strongly involved in immunosuppression in head and neck cancer and become new cancer treatment targets.

Academic Significance and Societal Importance of the Research Achievements

がん免疫治療は、外科的治療、放射線治療、抗がん剤治療に次ぐ、第4の治療法として認知されるに至ったが、その奏効率は20-30％であり、さらなる研究開発が必要とされている。オプジーボ、キイトルーダ等の免疫チェックポイント阻害剤が、現在、がん免疫治療の中心となっているが、近年、制御性T細胞(Treg)が新たな免疫治療薬開発における標的として注目されている。今回の研究において、免疫チェックポイント阻害剤と、Tregの制御による複合免疫療法が、頭頸部がんに対する新たな免疫療法として有効であることが示唆された。今後、更なる研究により、奏効率の向上が期待される。

Research Products

• [Journal Article] Immune-checkpoint molecules on regulatory T-cells as potential therapeutic target in head and neck squamous cell cancers. (2020)
  • Author(s): Suzuki S, Ogawa T, Sano R, Takahara T, Inukai D, Satou A, Tsuchida H, Yoshikawa K, Ueda R, Tsuzuki T
  • Journal Title: Cancer Sci. Volume: in press Issue: 6 Pages: 1943-1957
  • DOI: 10.1111/cas.14422
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combining T‐cell‐based immunotherapy with venetoclax elicits synergistic cytotoxicity to B‐cell lines in vitro (2020)
  • Author(s): Murakami Satsuki、Suzuki Susumu、Hanamura Ichiro、Yoshikawa Kazuhiro、Ueda Ryuzo、Seto Masao、Takami Akiyoshi
  • Journal Title: Hematological Oncology Volume: 38 Issue: 5 Pages: 705-714
  • DOI: 10.1002/hon.2794
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of tryptophan catabolism in follicular lymphoma (2020)
  • Author(s): Masaki Ayako、Ishida Takashi、Maeda Yasuhiro、Ito Asahi、Suzuki Susumu、Narita Tomoko、Kinoshita Shiori、Yoshida Takashi、Ri Masaki、Kusumoto Shigeru、Komatsu Hirokazu、Inagaki Hiroshi、Ueda Ryuzo、Choi Ilseung、Suehiro Youko、Iida Shinsuke
  • Journal Title: Hematological Oncology Volume: 38 Issue: 5 Pages: 742-753
  • DOI: 10.1002/hon.2804
  • Peer Reviewed / Open Access
• [Journal Article] Robust CD8+ T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma (2020)
  • Author(s): Saito Masato、Ishii Toshihiko、Urakawa Itaru、Matsumoto Asuka、Masaki Ayako、Ito Asahi、Kusumoto Shigeru、Suzuki Susumu、Takahashi Takeshi、Morita Akimichi、Inagaki Hiroshi、Iida Shinsuke、Ishida Takashi
  • Journal Title: Blood Advances Volume: 4 Issue: 10 Pages: 2180-2191
  • DOI: 10.1182/bloodadvances.2020001641
  • Peer Reviewed / Open Access
• [Journal Article] Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis. (2019)
  • Author(s): Watanabe M, Kanao K, Suzuki S, Muramatsu H, Morinaga S, Kajikawa K, Kobayashi I, Nishikawa G, Kato Y, Zennami K, Nakamura K, Tsuzuki T, Yoshikawa K, Ueda R, Sumitomo M.
  • Journal Title: Prostate Volume: 79(14) Issue: 14 Pages: 1658-1665
  • DOI: 10.1002/pros.23890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mogamulizumab treatment elicits autoantibodies attacking the skin in patients with adult T cell leukemia-lymphoma (2019)
  • Author(s): Suzuki Yui、Saito Masato、Ishii Toshihiko、Urakawa Itaru、Matsumoto Asuka、Masaki Ayako、Ito Asahi、Kusumoto Shigeru、Suzuki Susumu、Hiura Masanori、Takahashi Takeshi、Morita Akimichi、Inagaki Hiroshi、Iida Shinsuke、Ishida Takashi
  • Journal Title: Clinical Cancer Research Volume: 印刷中 Issue: 14 Pages: 4388-4399
  • DOI: 10.1158/1078-0432.ccr-18-2575
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunomodulatory and Metabolic Changes after Gnetin-C Supplementation in Humans. (2019)
  • Author(s): Nakagami Y, Suzuki S, Espinoza JL, Vu Quang L, Enomoto M, Takasugi S, Nakamura A, Nakayama T, Tani H, Hanamura I, Takami A
  • Journal Title: Nutrients Volume: 11 Issue: 6 Pages: 1403-1403
  • DOI: 10.3390/nu11061403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CCR4 expression in tumor-infiltrating regulatory T cells in patients with squamous cell carcinoma of the lung: A prognostic factor for relapse and survival (2019)
  • Author(s): Kubo A, Asai N, Suzuki S, Murotani K, Numanami H, Yoshikawa K, Ueda R, Yamaguchi E
  • Journal Title: Cancer Invest Volume: 37 Issue: 3 Pages: 163-73
  • DOI: 10.1080/07357907.2019.1582848
  • Peer Reviewed
• [Journal Article] Increased Tim-3+ T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients. (2018)
  • Author(s): Kato R, Yamasaki M, Urakawa S, Nishida K, Makino T, Morimoto-Okazawa A, Kawashima A, Iwahori K, Suzuki S, Ueda R, Mori M, Satoh T, Doki Y, Wada H.
  • Journal Title: Cancer Immunol Immunother. Volume: 67 Issue: 11 Pages: 1673-1683
  • DOI: 10.1007/s00262-018-2225-x
  • Peer Reviewed
• [Journal Article] Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals. (2018)
  • Author(s): Masaki A, Ishida T, Suzuki S, Ito A, Narita T, Kinoshita S, Ri M, Kusumoto S, Komatsu H, Inagaki H, Ueda R, Iida S.
  • Journal Title: Cancer Sci Volume: 109 Issue: 8 Pages: 2383-2390
  • DOI: 10.1111/cas.13654
  • Peer Reviewed / Open Access
• [Presentation] Synergistic Effect of Venetoclax for Antibody Dependent Cell Cytotoxicity By Daratumumab (2020)
  • Author(s): Ayano Nakamura, Susumu Suzuki, Masao Seto, Souichi Takasugi, Jo Kanasugi, Ichiro Hanamura, Ryuzo Ueda, Akiyoshi Takami
  • Organizer: 62nd ASH annual meeting
  • Int'l Joint Research
• [Presentation] PD-L1 expression mechanisms are heterogeneous in oral cancer (2020)
  • Author(s): Kondo Y, Suzuki S, Goto M, Ono Syoya, Ogawa T, Yoshikawa K, Tuzuki T, Ueda R
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Comparison of eTreg frequency status between metastatic and non-metastatic lymphnodes in head and neck cancer (2020)
  • Author(s): Ogawa T, Suzuki S, Sano R, Inukai D, Okamoto H, Takahara T, Yoshikawa K, Ueda R, Tsuzuki T
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Analysis of frequency and TCR repertoires of regulatory T-cell (Treg) of drain lymph node in head and neck cancer (2020)
  • Author(s): Suzuki S, Ogawa T, Sano R, Inukai D, Okamoto H, Takahara T, Sito M, Ishii T, Yoshikawa K, Ueda R, Tsuzuki T
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Development New Strategy for Head and Neck Immunotherapy from the Perspective of Translational and Reverse Translational Research (2019)
  • Author(s): Ogawa T, Okamoto H, Inukai D, Sano R, Yamanaka S, Ueda H, Takahara T, Tsuzuki T, Yoshikawa K, Suzuki S, Ueda R
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] New strategy of immunotherapy for head and neck squamous cell cancers (HNSCCs) combined with IC and Treg inhibitors. (2019)
  • Author(s): Suzuki S, Ogawa T, Inukai D, Okamoto H, Sano R, Takahara T, Satou A, Yoshikawa K, Tsuzuki T, Ueda R
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Characterization of tumor immune-microenvironmen (TIME) in papillary thyroid cancer (PTC). (2019)
  • Author(s): Okamoto H, Suzuki S, Ogawa T, Inukai D, Sano R, Takahara T, Satou A, Yoshikawa K, Tsuzuki T, Ueda R
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Characterization of immune-suppressive microenvironment in head & neck cancer. (2018)
  • Author(s): 1.Sano R, Suzuki S, Ogawa T, Inukai D, Okamoto H, Takahara T, Sato A, Yoshikawa K, Tsuzuki T, Ueda R.
  • Organizer: 第77回 日本癌学会総会
• [Presentation] Interim immunostaining results from phase I study of pre-operative combination therapy with mogamulizumab and nivolumab. (2018)
  • Author(s): 2.Suzuki S, Tsuzuki T, Ishida T, Kojima T, Kakimi K, Iida S, Oka M, Doki Y, Nishikawa H, Ueda R, and Wada H.
  • Organizer: 第77回 日本癌学会総会