Exploration of fatty acid metabolism that can activate immune checkpoint pathway in breast cancer

• Project/Area Number: 18K16254
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Kawashima Masahiro 京都大学, 医学研究科, 助教 (80766676)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 脂肪酸 / 免疫チェックポイント / 乳癌 / 温度 / 代謝 / 低酸素 / ストレス応答 / 放射線治療 / 熱 / 免疫 / 脂肪酸解析

Outline of Final Research Achievements

In this study, we explored the molecular mechanisms underlying the strong correlation between fatty acid metabolism and tumour immune activity in breast cancer tissue, as revealed by the analysis of clinical breast cancer samples. The results showed that the expression of a fatty acid binding protein, FABP7 in breast cancer cells 1) regulates the expression of PD-L1, a regulatory molecule of the immune checkpoint, 2) strongly determines the ability to proliferate from a single cell, 3) is involved in resistance to oxidative stress such as irradiation and hypoxia, 4) is involved in cellular heat production and temperature regulation. These results suggested that FABP7 and tumour immune activity do not simply correlate one-to-one, and that FABP7 regulates tumour immunity by modifying multiple cellular functions especially stress response and thermal metabolism.

Academic Significance and Societal Importance of the Research Achievements

FABP7が乳がん細胞の免疫反応、増殖能、幹細胞性、ストレス耐性、細胞温度など様々な機能を直接的あるいは間接的に制御していることが示唆された。特に、FABP7によるPD-L1の発現制御や温度制御との関連はこれまでに既報がない重要な発見であった。本研究で得られた知見を、今後乳がんの免疫療法の進歩にどのように繋げていくかについてはさらなる注意深い検証が必要であるが、乳がんの生物学に「温度と免疫と脂肪酸」という全く新しい概念を提示できたことは本研究の貴重な成果であると考えられた。

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University College Cork(アイルランド)
• [Int'l Joint Research] University of Oxford(英国)
• [Journal Article] Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells (2020)
  • Author(s): Kawashima Masahiro、Bensaad Karim、Zois Christos E.、Barberis Alessandro、Bridges Esther、Wigfield Simon、Lagerholm Christoffer、Dmitriev Ruslan I.、Tokiwa Mariko、Toi Masakazu、Papkovsky Dmitri B.、Buffa Francesca M.、Harris Adrian L.
  • Journal Title: Cancer & Metabolism Volume: 8 Issue: 1
  • DOI: 10.1186/s40170-020-00219-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correction to: Disruption of hypoxia-inducible fatty acid binding protein 7 induces beige fat-like differentiation and thermogenesis in breast cancer cells (2020)
  • Author(s): Kawashima Masahiro、Bensaad Karim、Zois Christos E.、Barberis Alessandro、Bridges Esther、Wigfield Simon、Lagerholm Christoffer、Dmitriev Ruslan I.、Tokiwa Mariko、Toi Masakazu、Papkovsky Dmitri B.、Buffa Francesca M.、Harris Adrian L.
  • Journal Title: Cancer & Metabolism Volume: 8 Issue: 1
  • DOI: 10.1186/s40170-020-00224-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-resolution imaging mass spectrometry combined with transcriptomic analysis identified a link between fatty acid composition of phosphatidylinositols and the immune checkpoint pathway at the primary tumour site of breast cancer. (2020)
  • Author(s): Kawashima M, Tokiwa M, Nishimura T, Kawata Y, Sugimoto M, Kataoka TR, Sakurai T, Iwaisako K, Suzuki E, Hagiwara M, Harris AL, Toi M.
  • Journal Title: Br J Cancer. Volume: 122 Issue: 2 Pages: 245-257
  • DOI: 10.1038/s41416-019-0662-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Fatty acid binding protein 7 regulates beige fat-like differentiation of breast cancer cells and thermogenesis (2020)
  • Author(s): Kawashima M, et al.
  • Organizer: AACR2020 Annual meeting
  • Int'l Joint Research
• [Presentation] 乳がん細胞による内因性熱産生機構 (2019)
  • Author(s): 川島雅央
  • Organizer: 第１回 日本癌学会若手の会
• [Presentation] High-resolution imaging mass spectrometry identified the missing link between fatty acid remodeling of phosphatidylinositols and the activity of PD1-related immune checkpoint pathway (2018)
  • Author(s): Masahiro Kawashima, Tomomi Nishimura, Yukiko Kawata, Eiji Suzuki, and Masakazu Toi
  • Organizer: Ｃｅｌｌ Ｓｙｍｐｏｓｉａ Ｔｒａｎｓｌａｔｉｏｎａｌ ｉｍｍｕｎｏｍｅｔａｂｏｌｉｓｍ
  • Int'l Joint Research
• [Presentation] 脂質代謝物は乳癌の新しいバイオマーカーとなるか？－高解像度質量顕微鏡の解析から見えてきた事－ (2018)
  • Author(s): 川島雅央、常盤麻里子、西村知美、川田有希子、片岡竜樹、桜井孝規、祝迫惠子、鈴木栄治、戸井雅和
  • Organizer: 第26回日本乳癌学会学術総会