Developing novel therapeutic strategy for the treatment of malignant pleural mesothelioma by targeting asbestos-indeced innate immune inflammation

• Project/Area Number: 18K15962
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Minami Toshiyuki 兵庫医科大学, 医学部, 講師 (00705113)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 悪性胸膜中皮腫 / 腫瘍関連マクロファージ / インフラマソーム / 癌幹細胞 / IL-1受容体 / アスベスト

Outline of Final Research Achievements

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Developing a novel therapeutic strategy has been a pressing issue to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared to normal mesothelial cells. Stimulation by pro-inflammatory cytokine IL-1β promoted MPM cells to form spheroids along with upregulating cancer stem cell marker CD26, indicating that IL-1β enhanced the malignant potential of MPM. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1β in MPM microenvironment. Immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with standard chemotherapy revealed that overexpression of IL-1R tended to correlate with poor overall survival. Collectively, interaction between MPM cells and TAMs through IL-1β/IL-1R signal could be a promising candidate as target for novel treatment of MPM.

Academic Significance and Societal Importance of the Research Achievements

悪性胸膜中皮腫（Malignant pleural mesothelioma: MPM）は難治性悪性腫瘍で、「発生」については、アスベストの関与が証明されているが、その「進展」にアスベストが関与しているかは解明されていない。
本研究では、アスベストが腫瘍関連マクロファージのインフラマソームを恒常的に活性化する事によって分泌される炎症性サイトカインIL-1βが、MPM細胞のIL-1Rを介してMPMの悪性度の促進、幹細胞化に関与している事が示唆された。
従って、IL-1β/IL-1Rのシグナルを抑制する事は、化学療法に対するMPM細胞の感受性を高め、予後の改善に繋がる可能性があると考えられた。

Research Products

• [Journal Article] A superior vena cava aneurysm discovered by chance at regular physical examination (2020)
  • Author(s): Nakajima Yasuhiro、Minami Toshiyuki、Ishigaki Hirotoshi、Sakai Eirou、Takahashi Ryo、Yokoi Takashi、Kuribayashi Kozo、Kijima Takashi
  • Journal Title: Respiratory Investigation Volume: - Issue: 4 Pages: 291-294
  • DOI: 10.1016/j.resinv.2019.12.002
  • Peer Reviewed
• [Journal Article] Tumor‐associated macrophage‐derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma (2020)
  • Author(s): Horio Daisuke、Minami Toshiyuki、Kitai Hidemi、Ishigaki Hirotoshi、Higashiguchi Yoko、Kondo Nobuyuki、Hirota Seiichi、Kitajima Kazuhiro、Nakajima Yasuhiro、Koda Yuichi、Fujimoto Eriko、Negi Yoshiki、Niki Maiko、Kanemura Shingo、Shibata Eisuke、Mikami Koji、Takahashi Ryo、Yokoi Takashi、Kuribayashi Kozo、Kijima Takashi
  • Journal Title: Cancer Science Volume: - Issue: 8 Pages: 2895-2906
  • DOI: 10.1111/cas.14523
  • Peer Reviewed / Open Access
• [Journal Article] EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest (2019)
  • Author(s): Ishigaki Hirotoshi、Minami Toshiyuki、Morimura Osamu、Kitai Hidemi、Horio Daisuke、Koda Yuichi、Fujimoto Eriko、Negi Yoshiki、Nakajima Yasuhiro、Niki Maiko、Kanemura Shingo、Shibata Eisuke、Mikami Koji、Takahashi Ryo、Yokoi Takashi、Kuribayashi Kozo、Kijima Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 519 Issue: 4 Pages: 846-853
  • DOI: 10.1016/j.bbrc.2019.09.076
  • Peer Reviewed
• [Journal Article] Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression (2019)
  • Author(s): Wettersten Hiromi I.、Weis Sara M.、Pathria Paulina、Von Schalscha Tami、Minami Toshiyuki、Varner Judith A.、Cheresh David A.
  • Journal Title: Cancer Research Volume: 79 Issue: 19 Pages: 5048-5059
  • DOI: 10.1158/0008-5472.can-19-1246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Challenges for the development of immunotherapy in small-cell lung cancer. (2018)
  • Author(s): Minami T, Kinehara Y, Morimura O, Kitai H, Fujimoto E, Negi Y, Kanemura S, Shibata E, Mikami K, Yokoi T, Kuribayashi K, Kijima T.
  • Journal Title: Med Res Arch. Volume: 6 Pages: 1-15
  • Peer Reviewed
• [Presentation] 微小環境中の腫瘍関連マクロファージにおけるインフラマソームが悪性胸膜中皮腫の進展に及ぼす役割 (2019)
  • Author(s): 堀尾大介、南 俊行、幸田裕一、袮木芳樹、二木麻衣子、柴田英輔、三上浩司、高橋 良、横井 崇、北島一宏、栗林康造、木島貴志
  • Organizer: 第1回 日本石綿・中皮腫学会
• [Presentation] 悪性胸膜中皮腫（Malignant Pleural Mesothelioma: MPM）微小環境中の腫瘍関連マクロファージにおけるインフラマソームの役割 (2019)
  • Author(s): 堀尾大介、南 俊行、幸田裕一、袮木芳樹、二木麻衣子、柴田英輔、三上浩司、高橋 良、横井 崇、栗林康造、木島貴志
  • Organizer: 第59回 日本呼吸器学会学術講演会
• [Presentation] 悪性胸膜中皮腫（Malignant Pleural Mesothelioma: MPM）微小環境中の腫瘍関連マクロファージにおけるインフラマソームの役割 (2019)
  • Author(s): 堀尾大介、南 俊行、幸田裕一、藤本英利子、祢木芳樹、金村晋吾、柴田英輔、三上浩司、高橋 良、横井 崇、栗林康造、木島貴志
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] 悪性胸膜中皮腫における腫瘍関連マクロファージのインフラマソームの役割 (2018)
  • Author(s): 堀尾大介、南 俊行、幸田裕一、藤本英利子、祢木芳樹、金村晋吾、柴田英輔、三上浩司、高橋 良、横井 崇、栗林康造、木島貴志1
  • Organizer: 第25回石綿・中皮腫研究会