Development of biomarkers related to drug resistance of angiogenesis inhibitors

• Project/Area Number: 20K08542
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: National Center for Global Health and Medicine (2022); The University of Tokushima (2020-2021)
• Principal Investigator: Nokihara Hiroshi 国立研究開発法人国立国際医療研究センター, センター病院, 呼吸器内科 医長 (00505919)
• Co-Investigator(Kenkyū-buntansha): 大塚 憲司 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (70776856) ; 三橋 惇志 徳島大学, 大学院医歯薬学研究部(医学域), 特任助教 (00833732)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 線維細胞 / 血管新生 / 免疫チェックポイント / ケモカイン / 薬剤耐性 / CXCLケモカイン / 血管新生阻害薬 / PD-L1抗体 / 非小細胞肺癌 / 間質性肺炎

Outline of Research at the Start

血管新生阻害薬は非小細胞肺がん患者に対して化学療法と併用して広く用いられている。しかし、血管新生阻害薬の耐性メカニズムの解明やバイオマーカーの同定は進んでいない。血管新生阻害薬の耐性において宿主から産生される線維芽細胞増殖因子が関与し、その産生細胞が線維細胞である。また、線維細胞は肺の病的線維化を促進する負の側面をもつ。本研究は、間質性肺炎合併非小細胞肺がんに対する血管新生阻害薬の有効性と安全性を検討する第Ⅱ相試験の附随研究として実施し、患者検体を用いて血管新生阻害薬の効果予測や耐性のバイオマーカー、及び間質性肺炎急性増悪のバイオマーカーとしての線維細胞の可能性を検討する。

Outline of Final Research Achievements

We found that fibrocytes express PD-L1, that they work as antigen-presenting cells, and that their antigen-presenting ability is enhanced by anti-PD-L1 antibodies (J Immunol. 2021). Furthermore, anti-VFGF antibody increases tumor-infiltrating fibrocytes and enhances the anti-tumor effect of anti-PD-L1 antibody, fibrocytes highly express co-stimulatory molecules, co-stimulatory activity of tumor-infiltrating fibrocytes is enhanced by anti-PD-L1 antibody, peritumoral implantation of fibrocytes enhances the anti-tumor effect of anti-PD-L1 antibody, and anti-PD-L1 antibody is effective against tumor-infiltrating fibrocytes, tumor-infiltrating fibroblasts acquire myofibroblast-like phenotypes through TGF-β/SMAD signaling (Cell Rep. 2023). In addition, we also found that anti-PD-L1 antibodies inhibit tumor angiogenesis via secretion of CXCL10/11 chemokines (Cancer Sci. 2021).

Academic Significance and Societal Importance of the Research Achievements

本研究は、血管新生阻害薬の効果予測や耐性のバイオマーカーとしての線維細胞の可能性を検討した。線維細胞に着目した血管新生阻害薬の有効性及び安全性に関わるバイオマーカー開発のアプローチは国内外ともに見当たらない。線維細胞の抗原提示細胞としての機能を明らかにしたこと、腫瘍浸潤線維細胞に対する抗PD-L1抗体による影響を明らかにしたこと、抗PD-L1抗体による腫瘍血管新生阻害することを明らかにしたことは、血管新生阻害薬や免疫チェックポイント阻害薬の効果予測や薬物耐性のバイオマーカー確立にも寄与する。さらには血管新生阻害薬や免疫チェックポイント阻害薬の個別化治療や新たな薬剤の開発につながると考えられる。

Research Products

• [Journal Article] Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade (2023)
  • Author(s): Mitsuhashi Atsushi, Koyama Kazuya, Ogino Hirokazu, Afroj Tania, Nguyen Na Thi, Yoneda Hiroto, Otsuka Kenji, Sugimoto Masamichi, Kondoh Osamu, Nokihara Hiroshi, Hanibuchi Masaki, Takizawa Hiromitsu, Shinohara Tsutomu, Nishioka Yasuhiko
  • Journal Title: Cell Reports Volume: 42 Issue: 3 Pages: 112162-112162
  • DOI: 10.1016/j.celrep.2023.112162
  • Peer Reviewed / Open Access
• [Journal Article] S‐1 eliminates <scp>MDSCs</scp> and enhances the efficacy of <scp>PD</scp> ‐1 blockade via regulation of tumor‐derived Bv8 and <scp>S100A8</scp> in thoracic tumor (2022)
  • Author(s): Nguyen Na T.、Mitsuhashi Atsushi、Ogino Hirokazu、Kozai Hiroyuki、Yoneda Hiroto、Afroj Tania、Sato Seidai、Nokihara Hiroshi、Shinohara Tsutomu、Nishioka Yasuhiko
  • Journal Title: Cancer Science Volume: 114 Issue: 2 Pages: 384-398
  • DOI: 10.1111/cas.15620
  • Peer Reviewed
• [Journal Article] Efficacy and safety of second‐line chemotherapy for patients with advanced non‐small cell lung cancer complicated by interstitial lung disease (2022)
  • Author(s): Otsuka Kenji、Nokihara Hiroshi、Mitsuhashi Atsushi、Ozaki Ryohiko、Yabuki Yohei、Yoneda Hiroto、Ogino Hirokazu、Nishioka Yasuhiko
  • Journal Title: Thoracic Cancer Volume: 13 Issue: 21 Pages: 2978-2984
  • DOI: 10.1111/1759-7714.14645
  • Peer Reviewed
• [Journal Article] Programmed death (PD)‐1/PD‐ligand 1 blockade mediates antiangiogenic effects by tumor‐derived CXCL10/11 as a potential predictive biomarker (2021)
  • Author(s): Mitsuhashi Atsushi、Kondoh Kensuke、Horikawa Kazuki、Koyama Kazuya、Nguyen Na Thi、Afroj Tania、Yoneda Hiroto、Otsuka Kenji、Ogino Hirokazu、Nokihara Hiroshi、Shinohara Tsutomu、Nishioka Yasuhiko
  • Journal Title: Cancer Science Volume: 112 Issue: 12 Pages: 4853-4866
  • DOI: 10.1111/cas.15161
  • Peer Reviewed / Open Access
• [Presentation] The examination of the second-line chemotherapy in SCLC patients with interstitial lung disease (2022)
  • Author(s): Ryohiko Ozaki, Hiroshi Nokihara, Youhei Yabuki, Atsushi Mitsuhashi, Hiroto Yoneda, Kenji Otsuka, Hirokazu Ogino, Yasuhiko Nishioka
  • Organizer: ERS International Congress 2022
  • Int'l Joint Research
• [Presentation] PD-1/PD-L1 blockade mediates antiangiogenic effects by tumorderived CXCL10/11 as a potential predictive biomarker (2022)
  • Author(s): Atsushi Mitsuhashi, Hirokazu Ogino, Hiroshi Nokihara, Yasuhika Nishioka
  • Organizer: 第81回日本癌学会学術総会
  • Invited