Development of novel immunotherapy by identification and proliferation of cervical cancer-specific stem cell memory T cells

• Project/Area Number: 18K16813
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Nihon University (2020); Keio University (2018-2019)
• Principal Investigator: KATOH Yuki 日本大学, 医学部, 助教 (60733649)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: ステムセルメモリーT細胞 / 免疫チェックポイント阻害薬 / 抗PD-1抗体療法 / 免疫チェックポイント阻害剤 / 免疫療法 / 子宮頸がん / 子宮頸癌

Outline of Final Research Achievements

Stem cell memory T (Tscm) cells are a novel subset of memory T cells. Compared with other memory T cells (e.g., central memory/ effector memory T cell), Tscm cells are less sensitive, long-lived, and proliferate quickly in response to antigenic stimulation to produce large numbers of effector T cells, which is expected to be applied to cancer immunotherapy. We investigated the mechanism of tumor antigen-specific CD8+ Tscm cells proliferation and the differentiation into effector T cells. Furthermore, we evaluated several candidates that might promote the proliferation of antigen-specific CD8+ Tscm cells, and found that these drugs enhanced the therapeutic effect of anti-PD-1 antibody in a tumor-bearing mouse model.

Academic Significance and Societal Importance of the Research Achievements

Tscm細胞の発生・増殖・分化のメカニズムは未だ不明な点が多いことから、本研究により得られた知見は、その理解に役立つものと考えている。さらに、抗PD-1抗体などの免疫チェックポイント阻害薬単独での奏効率は、効果を示すがん種においても20%程度であり、不応例に対する併用療法の開発が重要な課題となっているが、我々の同定した標的分子の阻害剤を併用することにより、より効果的な複合がん免疫療法の提供が可能となる。

Research Products

• [Journal Article] Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy (2020)
  • Author(s): Akiko Ohno, Takashi Iwata, Yuki Katoh, Shiho Taniguchi, Kohsei Tanaka, Hiroshi Nishio, Masaru Nakamura , Tohru Morisada, Guanliang Chen, Miyuki Saito, Tomonori Yaguchi, Yutaka Kawakami, Daisuke Aoki
  • Journal Title: Gynecol Oncol . Volume: 159 Issue: 2 Pages: 329-334
  • DOI: 10.1016/j.ygyno.2020.07.106
  • Peer Reviewed
• [Journal Article] GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab. (2020)
  • Author(s): Kato D, Yaguchi T, Iwata T, Katoh Y, Morii K, Tsubota K, Takise Y, Tamiya M, Kamada H, Akiba H, Tsumoto K, Serada S, Naka T, Nishimura R, Nakagawa T, Kawakami Y.
  • Journal Title: Elife. Volume: 9
  • DOI: 10.7554/elife.49392
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor homeobox D9 is involved in the malignant phenotype of cervical cancer through direct binding to the human papillomavirus oncogene promoter (2019)
  • Author(s): Hirao N, Iwata T, Tanaka K, Nishio H, Nakamura M, Morisada T, Morii K, Maruyama N, Katoh Y, Yaguchi T, Ohta S, Kukimoto I, Aoki D, Kawakami Y.
  • Journal Title: Gynecol Oncol Volume: 155 Issue: 2 Pages: 340-348
  • DOI: 10.1016/j.ygyno.2019.08.026
  • Peer Reviewed / Open Access
• [Presentation] Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy (2021)
  • Author(s): T.Iwata, H.Nishio, K.Tanaka, M. Nakamura, T.Morisada, G.Chen, Y.Katoh, D.Aoki
  • Organizer: SGO 2021 Annual Meeting on Women’s Cancer
  • Int'l Joint Research
• [Presentation] Enhancement of anti-tumor effects of PD-1/PD-L1 inhibitors by modulation of signaling and metabolism in tumor microenvironment. (2019)
  • Author(s): Yutaka Kawakami, Yuki Katoh, Tomonori Yaguchi
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
  • Invited
• [Presentation] 脂肪酸不飽和化酵素Stearoyl-CoA desaturase-1 (SCD-1)の阻害は抗腫瘍免疫応答を増強させ、抗PD-1抗体の効果を増強する (2019)
  • Author(s): 加藤侑希, 岩田卓, 今川遼太郎, 谷口智憲, 河上裕
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] CIN2病変部のCD4陽性細胞の浸潤密度およびP16発現率はCIN2の予後予測に有用である (2019)
  • Author(s): 村山直之, 岩田卓, 堀江和史, 村上諒典, 加藤侑希, 斎藤深雪,飯島朋子, 田中恒成, 西尾浩, 仲村勝, 林茂徳, 森定徹, 青木大輔
  • Organizer: 第61回日本婦人科腫瘍学会
• [Patent(Industrial Property Rights)] 癌患者への癌免疫療法を含む癌治療法の適応の有効性を判定するマーカー及びその使用 (2019)
  • Inventor(s): 谷口智憲、加藤侑希、久保亜紀子、河上裕
  • Industrial Property Rights Holder: 谷口智憲、加藤侑希、久保亜紀子、河上裕
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-106533
  • Filing Date: 2019