Exploration of molecular targets to regulate cancer-associated fibroblasts-mediated immunosuppression in the tumor microenvironment

• Project/Area Number: 17K11374
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Gunma University
• Principal Investigator: CHIKAMATSU KAZUAKI 群馬大学, 大学院医学系研究科, 教授 (30301378)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 頭頸部癌 / 癌関連線維芽細胞 / 癌

Outline of Final Research Achievements

Tumor cells create immunosuppressive network with various stromal cells in the tumor microenvironment. Among various types of stromal cells, cancer-associated fibroblasts (CAFs) have been recognized as one of key component for escape from host antitumor immunity. In this study, we detected AKT3 as a common molecule mediated immune suppression in both cancer cells and CAFs. AKT3 expression in tumor cells and CAFs was a prognostic factor in oral squamous cell carcinoma, respectively. Moreover, knockdown of AKT3 expression in tumor cells and CAFs resulted in significant inhibition of cellular proliferation, cytokine production, and expression of immune regulatory molecules.

Academic Significance and Societal Importance of the Research Achievements

がん局所は免疫抑制状態となっており、このことが治療抵抗性や予後不良と関係している。今回の研究において、癌細胞と癌関連線維芽細胞（CAFs）の免疫抑制機能を制御できる共通の分子（AKT3）が同定できたことにより、この分子を標的とした新規薬剤の開発につながる可能性がある。このような薬剤は効率的にがん局所の免疫抑制状態を改善させ、現在限定的な効果を示す免疫チェックポイント阻害剤との併用により、その治療効果の改善に寄与できるかもしれない。また、AKT3は予後予測因子としてのバイオマーカーとして利用できる可能性がある。

Research Products

• [Journal Article] Epithelial-mesenchymal transition status of circulating tumor cells is associated with tumor relapse in head and neck squamous cell carcinoma. (2020)
  • Author(s): Tada H, Takahashi H, Ida S. Nagata Y, Chikamatsu K.
  • Journal Title: Anticancer Res Volume: 40
  • Peer Reviewed
• [Journal Article] Molecular profiling of circulating tumor cells predicts clinical outcome in head and neck squamous cell carcinoma (2020)
  • Author(s): Tada Hiroe、Takahashi Hideyuki、Kuwabara-Yokobori Yuki、Shino Masato、Chikamatsu Kazuaki
  • Journal Title: Oral Oncology Volume: 102 Pages: 104558-104558
  • DOI: 10.1016/j.oraloncology.2019.104558
  • Peer Reviewed
• [Journal Article] Tongue surface model can predict radiation tongue mucositis due to intensity-modulated radiation therapy for head and neck cancer (2020)
  • Author(s): Musha A.、Fukata K.、Saitoh J.-I.、Shirai K.、Abe T.、Mizukami T.、Kawashima M.、Yokoo S.、Chikamatsu K.、Ohno T.、Nakano T.
  • Journal Title: International Journal of Oral and Maxillofacial Surgery Volume: 49 Issue: 1 Pages: 44-50
  • DOI: 10.1016/j.ijom.2019.06.012
  • Peer Reviewed
• [Journal Article] Carbon-ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study. (2019)
  • Author(s): Takayasu Y, Kubo N, Shino M, Nikkuni O, Ida S, Musha A, Takahashi K, Hirato J, Shirai K, Saitoh JI, Yokoo S, Chikamatsu K, Ohno T, Nakano T; Working Group on Head and Neck Tumors.
  • Journal Title: Cancer Med. Volume: 8 Issue: 17 Pages: 7227-7235
  • DOI: 10.1002/cam4.2614
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dosimetric parameters predictive of nasolacrimal duct obstruction after carbon-ion radiotherapy for head and neck carcinoma (2019)
  • Author(s): Kubo Nobuteru、Kubota Yoshiki、Kawamura Hidemasa、Oike Takahiro、Sakai Makoto、Kumazawa Takuya、Miyasaka Yuhei、Okazaki Shohei、Kobayashi Daijiro、Sato Hiro、Mizukami Tatsuji、Musha Atsushi、Shirai Katsuyuki、Saitoh Jun-ichi、Yokoo Satoshi、Chikamatsu Kazuaki、Ohno Tatsuya、Nakano Takashi
  • Journal Title: Radiotherapy and Oncology Volume: 141 Pages: 72-77
  • DOI: 10.1016/j.radonc.2019.07.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid Effect of Benralizumab for Hypereosinophilia in a Case of Severe Asthma with Eosinophilic Chronic Rhinosinusitis (2019)
  • Author(s): Tsurumaki、Matsuyama、Ezawa、Koga、Yatomi、Aoki-Saito、Chikamatsu、Hisada
  • Journal Title: Medicina Volume: 55 Issue: 7 Pages: 336-336
  • DOI: 10.3390/medicina55070336
  • Peer Reviewed / Open Access
• [Journal Article] Immunological and clinicopathological significance of MFG-E8 expression in patients with oral squamous cell carcinoma. (2019)
  • Author(s): Okamoto A, Sakakura K, Takahashi H, Motegi S, Kaira K, Yokobori-Kuwabara Y, Ishikawa O, Chikamatsu K.
  • Journal Title: Pathol Oncol Res Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Biological Significance of PD-L1 Expression Within the Tumor Microenvironment of Oral Squamous Cell Carcinoma (2019)
  • Author(s): TAKAHASHI HIDEYUKI、SAKAKURA KOICHI、ARISAKA YUKIKO、TOKUE AZUSA、KAIRA KYOICHI、TADA HIROE、HIGUCHI TETSUYA、OKAMOTO AYAKO、TSUSHIMA YOSHITO、CHIKAMATSU KAZUAKI
  • Journal Title: Anticancer Research Volume: 39 Issue: 6 Pages: 3039-3046
  • DOI: 10.21873/anticanres.13437
  • Peer Reviewed
• [Journal Article] Prognostic significance and population dynamics of peripheral monocytes in patients with oropharyngeal squamous cell carcinoma (2019)
  • Author(s): Takahashi Hideyuki、Sakakura Koichi、Tada Hiroe、Kaira Kyoichi、Oyama Tetsunari、Chikamatsu Kazuaki
  • Journal Title: Head & Neck Volume: 41 Issue: 6 Pages: 1880-1888
  • DOI: 10.1002/hed.25625
  • Peer Reviewed
• [Journal Article] Expression of immune-regulatory molecules in circulating tumor cells derived from patients with head and neck squamous cell carcinoma (2019)
  • Author(s): Chikamatsu Kazuaki、Tada Hiroe、Takahashi Hideyuki、Kuwabara-Yokobori Yuki、Ishii Hiroki、Ida Shota、Shino Masato
  • Journal Title: Oral Oncology Volume: 89 Pages: 34-39
  • DOI: 10.1016/j.oraloncology.2018.12.002
  • Peer Reviewed
• [Journal Article] Interleukin‐8 produced by T cells is under the control of dopamine signaling (2018)
  • Author(s): Matsuyama Toshiyuki、Kawano Masaaki、Takagi Rie、Nakagome Kazuyuki、Chikamatsu Kazuaki、Matsushita Sho
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: 9 Issue: 4 Pages: 251-257
  • DOI: 10.1111/cen3.12472
  • Peer Reviewed / Open Access
• [Journal Article] Ambient mass spectorometry-based detection system for tumor cells in human blood. (2018)
  • Author(s): Sakamoto K, Fujita Y, Chiakmatsu K, Tanaka S, Takeda S, Masuyama K, Yoshimura K, Ishii H.
  • Journal Title: Transl Cancer Res Volume: 7 Pages: 758-764
  • Peer Reviewed
• [Journal Article] Melanoma antigen family A4 protein produced by transgenic silkworms induces antitumor immune responses (2018)
  • Author(s): Motokawa Yoko、Kokubo Michifumi、Kuwabara Nobuo、Tatematsu Ken?Ichiro、Sezutsu Hideki、Takahashi Hideyuki、Sakakura Koichi、Chikamatsu Kazuaki、Takeda Shigeki
  • Journal Title: Experimental and Therapeutic Medicine Volume: 15 Pages: 2512-2518
  • DOI: 10.3892/etm.2018.5703
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies. (2017)
  • Author(s): Ishii H, Chikamatsu K, Igarashi S, Takahashi H, Sakamoto K, Higuchi H, Tanaka S, Matsuoka T, Masuyama K.
  • Journal Title: Translational Oncology Volume: 11(1) Issue: 1 Pages: 132-139
  • DOI: 10.1016/j.tranon.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Dose-volume histogram analysis of brainstem necrosis in head and neck tumors treated using carbon-ion radiotherapy (2017)
  • Author(s): Shirai Katsuyuki、Fukata Kyohei、Adachi Akiko、Saitoh Jun-ichi、Musha Atsushi、Abe Takanori、Kanai Tatsuaki、Kobayashi Daijiro、Shigeta Yuka、Yokoo Satoshi、Chikamatsu Kazuaki、Ohno Tatsuya、Nakano Takashi
  • Journal Title: Radiother Oncol. Volume: 125 Issue: 1 Pages: 36-40
  • DOI: 10.1016/j.radonc.2017.08.014
  • Peer Reviewed / Open Access
• [Journal Article] Circulating tumor cells in patients with head and neck squamous cell carcinoma: Feasibility of detection and quantitation (2017)
  • Author(s): Kawada Tomoyuki、Takahashi Hideyuki、Sakakura Koichi、Ida Shota、Mito Ikko、Toyoda Minoru、Chikamatsu Kazuaki
  • Journal Title: Head & Neck Volume: 39 Issue: 11 Pages: 2180-2186
  • DOI: 10.1002/hed.24893
  • Peer Reviewed / Open Access
• [Journal Article] Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck. (2017)
  • Author(s): Shirai K, Saitoh J, Musha A, Abe T, Kobayashi D, Takahashi T, Tamaki T, Kawamura H, Takayasu Y, Shino M, Toyoda M, Takahashi K, Hirato J, Yokoo S, Chikamatsu K, Ohno T, Nakano T
  • Journal Title: Cancer Science Volume: 108 Issue: 10 Pages: 2039-2044
  • DOI: 10.1111/cas.13325
  • Peer Reviewed / Open Access
• [Presentation] Detection and molecular characterization of circulating tumor cells in advanced head and neck squamous cell carcinoma. (2019)
  • Author(s): Tada H, Takahashi H, Ishi H, Kuwabara Y, Shino M, Chikamatsu K.
  • Organizer: AACR 2019
  • Int'l Joint Research
• [Presentation] 頭頸部扁平上皮癌の循環癌細胞における免疫抑制機構の検討 (2019)
  • Author(s): 近松一朗、多田紘恵、高橋秀行、石井裕貴、桑原有紀、紫野正人
  • Organizer: 第120回日本耳鼻咽喉科学会総会
• [Presentation] 進行頭頸部扁平上皮癌患者における循環癌細胞の同定とその臨床的意義について (2019)
  • Author(s): 多田 紘恵、高橋 秀行、近松 一朗
  • Organizer: 第78回日本癌学会
• [Presentation] トランスクリプトーム解析によるがん免疫微小環境の解明と複合がん免疫療法開発への応用 (2018)
  • Author(s): 近松一朗
  • Organizer: 第119回日本耳鼻咽喉科学会総会・学術講演会
• [Presentation] Immunological characteristics of circulating tumor cells in patients with head and neck squamous cell carcinoma (2018)
  • Author(s): Tada Hiroe, Takahashi Hideyuki, Ishii Hiroki, Kuwabara-Yokobori Yuki, Ida Shota, Shino Masato, Chikamatsu Kazuaki.
  • Organizer: AACR Special Conference on Tumor Immunology and Immunotherapy
  • Int'l Joint Research
• [Presentation] PI3KCA/AKT3 シグナリングを介した舌癌制御の可能性 (2017)
  • Author(s): 近松一朗
  • Organizer: 第30回日本口腔・咽頭科学会
• [Presentation] Comparison of curative surgery and carbon ion radiotherapy as an initial treatment for patients with carcinoma of the parotid gland. (2017)
  • Author(s): Sakurai M, Takayasu Y, Shino M, Sakakura K, Shirai K, Saitoh J, Ohno T, Nakano T, Chikamatsu K
  • Organizer: IFOS World Congres 2017
  • Int'l Joint Research
• [Presentation] 癌関連線維芽細胞における治療標的分子としてのAkt3の可能性 (2017)
  • Author(s): 高橋秀行、坂倉浩一、川端麗華、六代 範、西山正彦、近松一朗
  • Organizer: 頭頸部癌学会