The development of innovative radiotherapy by inhibiting IL-6 signaling for refractory oral cancer eradication

• Project/Area Number: 18H03005
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Nakayama Hideki 熊本大学, 大学院生命科学研究部(医), 教授 (70381001)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: IL-6 / 放射線療法 / 口腔扁平上皮癌 / 放射線耐性 / IL-6シグナル / がん微小環境 / 口腔癌 / 治療抵抗性

Outline of Final Research Achievements

X-ray irradiation under tocilizumab treatment in OSCC xenograft and PDX in vivo models demonstrated that tocilizumab augments the effect of X-ray irradiation and attenuates the level of radiation-induced dermatitis. It is likely that the effects of tocilizumab are brought about by reduced antioxidant activity of Nrf2-antioxidant pathway and decreased IL-6 expression. Radiotherapy under the treatment of tocilizumab can be largely expected to clinically apply in OSCC patients as a promising novel therapy.

Academic Significance and Societal Importance of the Research Achievements

OSCCに対するトシリズマブ併用の放射線療法の開発は世界発の試みである。トシリズマブは安全性や体内動態が確認された既存薬であり、ドラッグリポジショニングで臨床応用を図ることは、新薬の開発と比べてコスト面で大きな利点となる。放射線治療時にトシリズマブを同時に投与することにより、放射線の抗腫瘍効果を増強し、口腔粘膜炎や皮膚炎を軽くできることから、本研究結果は学術的・社会的に大きな意義を有する。

Research Products

• [Journal Article] Colonization of distant organs by tumor cells generating circulating homotypic clusters adaptive to fluid shear stress (2021)
  • Author(s): Maeshiro M, Shinriki S, Liu R, Nakachi Y, Komohara Y, Fujiwara Y, Ohtsubo K, Yoshida R, Iwamoto K, Nakayama H, Matsui H.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 6150-6150
  • DOI: 10.1038/s41598-021-85743-z
  • Peer Reviewed / Open Access
• [Journal Article] Can MRI-derived depth of invasion predict nodal recurrence in oral tongue cancer? (2021)
  • Author(s): Minamitake Anri、Murakami Ryuji、Sakamoto Fumi、Yoshida Ryoji、Sakata Junki、Hirosue Akiyuki、Kawahara Kenta、Yamana Keisuke、Nakayama Hideki、Toya Ryo、Shiraishi Shinya
  • Journal Title: Oral Radiology Volume: - Issue: 4 Pages: 641-646
  • DOI: 10.1007/s11282-020-00505-3
  • Peer Reviewed / Open Access
• [Journal Article] Postoperative delirium in patients undergoing tumor resection with reconstructive surgery for oral cancer (2021)
  • Author(s): Takahashi Nozomu、Hiraki Akimitsu、Kawahara Kenta、Nagata Masashi、Yoshida Ryoji、Matsuoka Yuichiro、Tanaka Takuya、Obayashi Yuko、Sakata Junki、Nakashima Hikaru、Arita Hidetaka、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Molecular and Clinical Oncology Volume: 14 Issue: 3 Pages: 60-60
  • DOI: 10.3892/mco.2021.2222
  • Peer Reviewed / Open Access
• [Journal Article] Onodera's prognostic nutritional index correlates with tumor immune environment and survival in patients with oral squamous cell carcinoma undergoing chemoradiotherapy (2020)
  • Author(s): Yoshida Ryoji、Gohara Shunsuke、Sakata Junki、Matsuoka Yuichiro、Hirosue Akiyuki、Kawahara Kenta、Kawaguchi Sho、Nagao Yuka、Yamana Keisuke、Nagata Masashi、Fukuma Daiki、Toya Ryo、Murakami Ryuji、Hiraki Akimitsu、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Translational Oncology Volume: 13 Issue: 12 Pages: 100850-100850
  • DOI: 10.1016/j.tranon.2020.100850
  • Peer Reviewed / Open Access
• [Journal Article] Compositional Shift of Oral Microbiota Following Surgical Resection of Tongue Cancer (2020)
  • Author(s): Kageyama Shinya、Nagao Yuka、Ma Jiale、Asakawa Mikari、Yoshida Ryoji、Takeshita Toru、Hirosue Akiyuki、Yamashita Yoshihisa、Nakayama Hideki
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 10 Pages: 60084-60084
  • DOI: 10.3389/fcimb.2020.600884
  • Peer Reviewed / Open Access
• [Journal Article] Role of serum amylase and salivary cytokines in oral complications during chemoradiotherapy (2020)
  • Author(s): Kawahara Kenta、Hiraki Akimitsu、Arita Hidetaka、Takeshita Hisashi、Hirosue Akiyuki、Matsuoka Yuichiro、Sakata Junki、Obayashi Yuko、Nakashima Hikaru、Hirayama Mayumi、Nagata Masashi、Yoshida Ryoji、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Oral Diseases Volume: Online ahead of print Issue: 6 Pages: 1564-1571
  • DOI: 10.1111/odi.13686
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Features of Disaster-Associated Direct Deaths during Recent Inland Earthquakes in Japan (2020)
  • Author(s): Naito Hisaki、Sueta Daisuke、Nakayama Hideki、Araki Eiichi、Tanihara Hidenobu、Kasaoka Shunji、Tsujita Kenichi
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 251 Issue: 3 Pages: 169-173
  • DOI: 10.1620/tjem.251.169
  • NAID: 130007871484
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene (2020)
  • Author(s): Yamamoto Tatsuro、Hirosue Akiyuki、Nakamoto Masafumi、Yoshida Ryoji、Sakata Junki、Matsuoka Yuichiro、Kawahara Kenta、Nagao Yuka、Nagata Masashi、Takahashi Nozomu、Hiraki Akimitsu、Shinohara Masanori、Nakao Mitsuyoshi、Saitoh Noriko、Nakayama Hideki
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 4 Pages: 580-590
  • DOI: 10.1038/s41416-020-0907-6
  • Peer Reviewed / Open Access
• [Journal Article] Hypofractionated palliative volumetric modulated arc radiotherapy with the Radiation Oncology Study Group 8502 “QUAD shot” regimen for incurable head and neck cancer (2020)
  • Author(s): Toya Ryo、Saito Tetsuo、Yamaguchi Kohsei、Matsuyama Tomohiko、Watakabe Takahiro、Matsumoto Tadashi、Yoshida Ryoji、Hirosue Akiyuki、Murakami Daizo、Orita Yorihisa、Nakayama Hideki、Oya Natsuo
  • Journal Title: Radiation Oncology Volume: 15 Issue: 1 Pages: 123-123
  • DOI: 10.1186/s13014-020-01548-w
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of adjuvant chemotherapy with S-1 in stage II oral squamous cell carcinoma patients: A comparative study using the propensity score matching method (2020)
  • Author(s): Ryoji Yoshida, Masashi Nagata, Akiyuki Hirosue, Kenta Kawahara, Masafumi Nakamoto, Masatoshi Hirayama, Nozomu Takahashi, Yuichiro Matsuoka, Junki Sakata, Hikaru Nakashima, Hidetaka Arita, Akimitsu Hiraki, Masanori Shinohara, Ken Kikuchi, Hideki Nakayama
  • Journal Title: PLoS One Volume: 15 Issue: 4 Pages: e0231656-e0231656
  • DOI: 10.1371/journal.pone.0231656
  • Peer Reviewed / Open Access
• [Journal Article] FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression (2020)
  • Author(s): Hirayama Mayumi、Wei Fan-Yan、Chujo Takeshi、Oki Shinya、Yakita Maya、Kobayashi Daiki、Araki Norie、Takahashi Nozomu、Yoshida Ryoji、Nakayama Hideki、Tomizawa Kazuhito
  • Journal Title: Cell Reports Volume: 31 Issue: 1 Pages: 107464-107464
  • DOI: 10.1016/j.celrep.2020.03.028
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma (2020)
  • Author(s): Sakata J, Hirosue A, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, Yamamoto T, Nagata M, Kawaguchi S, Gohara S, Nagao Y, Yamana K, Toya R, Murakami R, Kuwahara Y, Fukumoto M, Nakayama H
  • Journal Title: Cancers (Basel) Volume: 12(2) Issue: 2 Pages: 494-494
  • DOI: 10.3390/cancers12020494
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Features of Patients with Acute Aortic Dissection After an Earthquake ～Experience from The Kumamoto Earthquake 2016～ (2020)
  • Author(s): Komorita Takashi、Fujisue Koichiro、Sueta Daisuke、Sakamoto Kenji、Yamamoto Eiichiro、Hashimoto Yoichiro、Sakamoto Tomohiro、Tsunoda Ryusuke、Uesugi Hideyuki、Suzuki Ryusuke、Naito Hisaki、Hanzawa Kazuhiko、Araki Eiichi、Nakayama Hideki、Kasaoka Shunji、Hokimoto Seiji、Fukui Toshihiro、Tsujita Kenichi
  • Journal Title: American Journal of Hypertension Volume: 33 (3) Issue: 3 Pages: 261-268
  • DOI: 10.1093/ajh/hpz183
  • Peer Reviewed / Open Access
• [Journal Article] FOXP3 lymphocyte status may predict the risk of malignant transformation in oral leukoplakia (2020)
  • Author(s): Sakata Junki、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Hirosue Akiyuki、Naito Hisaki、Takeshita Hisashi、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Yamana Keisuke、Hiraki Akimitsu、Shinohara Masanori、Ito Takaaki、Nakayama Hideki
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32 Issue: 1 Pages: 33-39
  • DOI: 10.1016/j.ajoms.2019.06.005
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic Value of FDG-PET/CT for the Identification of Extranodal Extension in Patients With Head and Neck Squamous Cell Carcinoma (2020)
  • Author(s): Toya, R. Saito, T. Matsuyama, T. Kai, Y. Shiraishi, S. Murakami, D. Yoshida, R. Watakabe, T. Sakamoto, F. Tsuda, N. Arimura, H. Orita, Y. Nakayama, H. Oya, N.
  • Journal Title: Anticancer Res Volume: 40 Issue: 4 Pages: 2073-2077
  • DOI: 10.21873/anticanres.14165
  • Peer Reviewed / Open Access
• [Journal Article] Reliability of MRI-Derived Depth of Invasion of Oral Tongue Cancer (2019)
  • Author(s): Murakami Ryuji、Shiraishi Shinya、Yoshida Ryoji、Sakata Junki、Yamana Keisuke、Hirosue Akiyuki、Uchiyama Yoshikazu、Nakayama Hideki、Yamashita Yasuyuki
  • Journal Title: Academic Radiology Volume: 印刷中 Issue: 7 Pages: 30423-9
  • DOI: 10.1016/j.acra.2018.08.021
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of cancer invasion and growth via the C5a-C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion. (2019)
  • Author(s): Yoneda M, Imamura R, Nitta H, Taniguchi K, Saito F, Kikuchi K, Ogi H, Tanaka T, Katabuchi H, Nakayama H, Imamura T.
  • Journal Title: Oncol Lett. Volume: 17 Pages: 913-20
  • DOI: 10.3892/ol.2018.9715
  • Peer Reviewed
• [Journal Article] Circulating miRNA-1290 as a potential biomarker for response to chemoradiotherapy and prognosis of patients with advanced oral squamous cell carcinoma: A single-center retrospective study (2019)
  • Author(s): Nakashima H, Yoshida R, Hirosue A, Kawahara K, Sakata J, Arita H, Yamamoto T, Toya R, Murakami R, Hiraki A, Shinohara M, Ito T, Kuwahara Y, Nakayama H
  • Journal Title: Tumour Biol Volume: 41(3) Issue: 3 Pages: 1-10
  • DOI: 10.1177/1010428319826853
  • Peer Reviewed / Open Access
• [Journal Article] Bladder cancer-associated cancer-testis antigen-derived long peptides encompassing both CTL and promiscuous HLA class II-restricted Th cell epitopes induced CD4+ T cells expressing converged T-cell receptor genes in vitro (2018)
  • Author(s): Tsuruta Miki、Ueda Shohei、Yew Poh Yin、Fukuda Isao、Yoshimura Sachiko、Kishi Hiroyuki、Hamana Hiroshi、Hirayama Masatoshi、Yatsuda Junji、Irie Atsushi、Senju Satoru、Yuba Eiji、Kamba Tomomi、Eto Masatoshi、Nakayama Hideki、Nishimura Yasuharu
  • Journal Title: OncoImmunology Volume: 7 Issue: 4 Pages: 1415687-1415687
  • DOI: 10.1080/2162402x.2017.1415687
  • Peer Reviewed / Open Access
• [Journal Article] Tumor budding as a novel predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma (2018)
  • Author(s): Sakata Junki、Yamana Keisuke、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Nagata Masashi、Hirosue Akiyuki、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Hiraki Akimitsu、Shinohara Masanori、Toya Ryo、Murakami Ryuji、Nakayama Hideki
  • Journal Title: Human Pathology Volume: 76 Pages: 1-8
  • DOI: 10.1016/j.humpath.2017.12.021
  • Peer Reviewed / Open Access
• [Journal Article] Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma (2018)
  • Author(s): Shinriki S, Jono H, Maeshiro M, Nakamura T, Guo J, Li JD, Ueda M, Yoshida R, Shinohara M, Nakayama H, Matsui H, Ando Y.
  • Journal Title: Journal of Pathology Volume: 244 Issue: 3 Pages: 367-379
  • DOI: 10.1002/path.5019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of the image quality of turbo spin echo- and echo-planar diffusion-weighted images of the oral cavity. (2018)
  • Author(s): Hirata K, Nakaura T, Okuaki T, Kidoh M, Oda S, Utsunomiya D, Namimoto T, Kitajima M, Nakayama H, Yamashita Y.
  • Journal Title: Medicine (Baltimore) Volume: 97 Issue: 19 Pages: e0447-e0447
  • DOI: 10.1097/md.0000000000010447
  • Peer Reviewed
• [Journal Article] Giant cell reparative granuloma of the mandibular condyle: A rare presentation and literature review (2018)
  • Author(s): Segami N, Ogi H, Nakayama H, Nojima T.
  • Journal Title: Oral and Maxillofacial Surgery Cases Volume: 4 Issue: 4 Pages: 130-4
  • DOI: 10.1016/j.omsc.2018.08.003
  • Peer Reviewed
• [Journal Article] Severe interstitial pneumonia associated with anti-PD-1 immune checkpoint antibody after talc slurry pleurodesis (2018)
  • Author(s): Sakata Shinya、Matsuoka Yuichiro、Kawahara Kenta、Kakiuchi Yosuke、Takaki Akira、Hirosue Akiyuki、Yoshida Ryoji、Saeki Sho、Fujii Kazuhiko、Nakayama Hideki
  • Journal Title: Respiratory Investigation Volume: 56 Issue: 2 Pages: 195-198
  • DOI: 10.1016/j.resinv.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Mucinous adenocarcinoma with signet ring cell features of the sublingual gland: A case report with an immunohistochemical analysis (2018)
  • Author(s): Nagata Masashi、Kusafuka Kimihide、Yoshida Ryoji、Kawahara Kenta、Nakagawa Yoshihiro、Nakamoto Masafumi、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: - Issue: 3 Pages: 252-6
  • DOI: 10.1016/j.ajoms.2017.12.008
  • Peer Reviewed
• [Presentation] Research on overcoming radiation resistance of oral squamous cell carcinoma using anti-tumor virus and development of new treatment (2020)
  • Author(s): 郷原俊輔、吉田遼司、山名啓介、川口翔、永尾優果、平山真敏、川原健太、永田将士、廣末晃之、福間大喜、中山秀樹
  • Organizer: 第65回 日本口腔外科学会
• [Presentation] Colonization of distant organs by mechanosensitive tumor cells via generation of stable circulating homotypic clusters (2020)
  • Author(s): 前城 学、神力 悟、劉隣、仲地ゆたか、菰原義弘、藤原章雄、大坪和明、吉田遼司、中山秀樹、松井啓隆
  • Organizer: 第79回 日本癌学会
• [Presentation] Interactions of calcium with mitochondria contribute to cisplatin resistance in oral cancer (2020)
  • Author(s): Mayumi Hirayama, Kenata Kawahara, Akiyuki Hirosue, Satoru Shinriki, Ryoji Yoshida, Hirotaka Matsui and Hideki Nakayama
  • Organizer: 第79回 日本癌学会
• [Presentation] E3 ubiquitin ligase Riplet suppresses T cell-mediated anti-tumor response despite the increased activity of T cells (2020)
  • Author(s): Asuka Iwamoto, Hirotake Tsukamoto, Hideki Nakayama, Hiroyuki Oshiumi
  • Organizer: 第79回 日本癌学会
• [Presentation] Development of a prediction system for delayed neck metastases of tongue cancer (2020)
  • Author(s): Junki Inoue, Ryoji Yoshida, Junki Sakata, Kenta Kawahara, Masatoshi Hirayama, Akiyuki Hirosue, Masashi Nagata, Hideki Nakayama
  • Organizer: 第79回 日本癌学会
• [Presentation] 高度メカノセンシティブ腫瘍細胞は安定な循環ホモクラスター形成を介して遠隔臓器に定着する (2020)
  • Author(s): 前城 学、神力 悟、劉隣、仲地ゆたか、菰原義弘、藤原章雄、大坪和明、吉田遼司、中山秀樹、松井啓隆
  • Organizer: 第65回 日本口腔外科学会
• [Presentation] IL-6シグナル阻害剤トリシズマブは口腔扁平上皮癌の放射線感受性を増感する (2019)
  • Author(s): 松岡祐一郎
  • Organizer: 日本口腔外科学会
• [Presentation] 口腔扁平上皮癌におけるトシリズマブの放射線感受性効果の検討(Investigation of the effect of tocilizumab on radiosensitivity in oral squamous cell carcinoma) (2018)
  • Author(s): 有田 英生, 吉田 遼司, 松岡 祐一郎, 廣末 晃之, 永田 将士, 川原 健太, 坂田 純基, 中嶋 光, 川口 翔, 郷原 俊輔, 永尾 優果, 山名 啓介, 中山 秀樹
  • Organizer: 日本癌学会
• [Presentation] IL-6はマウス由来の口腔扁平上皮癌細胞株において、放射線抵抗性に関与する(Interleukin-6 confers radioresistance phenotype on Sq-1979 cells: mouse-derived oral squamous cell carcinoma cell line) (2018)
  • Author(s): 山名 啓介, 吉田 遼司, 坂田 純基, 松岡 祐一郎, 川原 健太, 有田 英生, 中嶋 光, 廣末 晃之, 川口 翔, 郷原 俊輔, 永尾 優果, 中山 秀樹
  • Organizer: 日本癌学会
• [Presentation] 抗酸化ストレス調節因子Nrf2は口腔扁平上皮癌の放射線耐性を制御する(Nrf2, anti-oxidative stress-regulatory factor, controls resistance to radiation in oral squamous cell carcinoma)(英語)( (2018)
  • Author(s): 松岡 祐一郎, 吉田 遼司, 廣末 晃之, 永田 将士, 川原 健太, 坂田 純基, 有田 英生, 中嶋 光, 平木 昭光, 篠原 正徳, 中山 秀樹
  • Organizer: 日本癌学会
• [Presentation] 口腔扁平上皮癌におけるIL-6、IL-6Rシグナリングによる放射線感受性効果の有用性 (2018)
  • Author(s): 有田 英生, 吉田 遼司, 松岡 祐一郎, 廣末 晃之, 永田 将士, 川原 健太, 中嶋 光, 坂田 純基, 郷原 俊輔, 永尾 優果, 川口 翔, 山名 啓介, 中山 秀樹
  • Organizer: 日本口腔科学会