A role of AhR signaling in NKT cell based immunotherapy for lung cancer

• Project/Area Number: 18K16409
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Chiba University
• Principal Investigator: Takami Mariko 千葉大学, 大学院医学研究院, 助教 (60770906)
• 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: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: NKT細胞 / 免疫療法 / AhRシグナル / 肺癌

Outline of Final Research Achievements

To improve our current iNKT cell-based immunotherapy for lung cancer, I sought to develop the combination therapy of iNKT cell-based immunotherapy using aryl hydrocarbon receptor (AhR) signaling. I initially focused on the fact that AhR signaling downregulated PD-L1/PD-L2 expression on monocyte-derived dendritic cells and enhanced antitumor activity of iNKT cells. However, the effect of iNKT cell-based immunotherapy was enhanced by adding AhR antagonist instead of AhR agonist in the CT26 s.c. mouse model in vivo. Furthermore, IFN-γ producing cells in CD8+ T cells was increased. These data suggest that the combination of AhR antagonist and iNKT cell-based immunotherapy can be a better treatment option for cancer patients than the current iNKT cell-based immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

我々の研究施設では、NKT細胞を用いた癌免疫療法の臨床応用として、α-GalCerをパルスした樹状細胞投与によりin vivoでNKT細胞を活性化させ抗腫瘍効果を上げる臨床試験を実施し一定の患者における全生存期間の延長が認められるなどの効果を上げてきた。本研究は、肺癌に対するNKT細胞療法の有効性の向上のため新たな併用免疫療法の開発を目的とした。AhRシグナルに着目し、AhRアンタゴニスト投与とNKT細胞療法の併用という新規治療法の可能性を、マウス腫瘍モデルを用いて示唆したことから学術的、社会的に意義のある成果を上げたと考える。

Research Products

• [Journal Article] Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer (2020)
  • Author(s): Toyoda, T., Kamata, T., Tanaka, K., Ihara, F., Takami, M., Suzuki, H., Nakajima, T., Ikeuchi, T., Kawasaki, Y., Hanaoka, H., Nakayama, T., Yoshino, I., and Motohashi, S.
  • Journal Title: J. Immunother. Cancer Volume: 8 Issue: 1 Pages: e000316-e000316
  • DOI: 10.1136/jitc-2019-000316
  • Peer Reviewed / Open Access
• [Journal Article] Immunological Features of a Lung Cancer Patient Achieving an Objective Response with Anti-PD-1 Blockade Therapy (2019)
  • Author(s): Kamata, T., Yoshida, S., Takami, M., Ihara, F., Yoshizawa, H., Toyoda, T., Takeshita, Y., Nobuyama, S., Kanetsuna, Y., Sato, T., Yoshino, I., and Motohashi, S.
  • Journal Title: Cancer Sci. Volume: 111 Issue: 1 Pages: 288-296
  • DOI: 10.1111/cas.14222
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells induce CD4－ NKT cell anergy and suppress NKT cell cytotoxic function (2019)
  • Author(s): Ihara, F., Sakurai, D., Takami, M., Kamata, T., Kunii, N., Yamasaki, K., Iinuma, T., Nakayama, T., Motohashi, S., and Okamoto, Y.
  • Journal Title: Cancer Immunol. Immunother Volume: 68 Issue: 12 Pages: 1935-1947
  • DOI: 10.1007/s00262-019-02417-6
  • Peer Reviewed / Open Access
• [Journal Article] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): Harada, K., Ihara, F., Takami, M., Kamata, T., Mise, N., Yoshizawa, H., Hishiki, T., Saito, T., Terui, K., Nakata, M., Komatsu, S., Ikeuchi, T., Nakayama, T., Yoshida, H., Motohashi, S.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 3 Pages: 888-902
  • DOI: 10.1111/cas.13933
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Application of iNKT Cell-mediated Anti-tumor Activity Against Lung Cancer and Head and Neck Cancer (2018)
  • Author(s): Takami, M., Ihara, F., Motohashi, S.
  • Journal Title: Front. Immunol. Volume: 7 Pages: 2021-2021
  • DOI: 10.3389/fimmu.2018.02021
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β suppresses RasGRP1 expression and supports regulatory T cells resistance against p53-induced CD28-dependent T cell apoptosis (2018)
  • Author(s): Takami, M., Cunha, C., Motohashi , S., Nakayama, T., Iwashima, M.
  • Journal Title: Eur. J. Immunol. Volume: 48 Issue: 12 Pages: 1938-1943
  • DOI: 10.1002/eji.201847587
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer (2018)
  • Author(s): Tanaka K, Kanesaka Y, Takami M, Suzuki A, Hosokawa H, Onodera A, Kamata T, Nagato K, Nakayama T, Yoshino I, Motohashi S
  • Journal Title: Biochem Biophys Res Commun. Volume: 506(1) Issue: 1 Pages: 27-32
  • DOI: 10.1016/j.bbrc.2018.10.048
  • Peer Reviewed
• [Presentation] 膠芽腫に発現するCD1d分子はNKT細胞を用いた免疫療法における有望な標的となる (2019)
  • Author(s): 原彩佳, 那須亮, 高見真理子, 小林正芳, 廣野誠一郎, 松谷智郎, 中山俊憲, 本橋新一郎, 岩立康男
  • Organizer: 日本脳神経外科学会第78回学術総会
• [Presentation] CD1d expression in glioblastoma is a promising target for NKT cell- based cancer immunotherapy (2019)
  • Author(s): Hara, A., Nasu, R., Takami, M., Hirono, S., Matsutani, T., Nakayama, T., Iwadate, Y., Motohashi, S.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] CD1d expression in glioblastoma is a promising target for NKT cell- based cancer immunotherapy (2019)
  • Author(s): Hara, A., Nasu, R., Takami, M., Hirono, S., Matsutani, T., Nakayama, T., Iwadate, Y., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Invariant NKT cells target CD1d-negative leukemia cells with TCR and NK receptors (2019)
  • Author(s): Aoki, T., Takami, M., Takatani, T., Motoyoshi, K., Ishii, A., Hara, A., Hino, M., Shimojo, N., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): Yoshizawa, H., Harada, K., Ishii, A., Mise, N., Hishiki, T., Saito, K., Nakata, M., Komatsu, S., Nakayama, T., Yoshida, H., Takami,M., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] NK cells enhance the anti-tumor activity of NKT cells (2019)
  • Author(s): Takami, M., Ihara, F., Ishii, A., Motohashi, S.
  • Organizer: EMBO workshop CD1-MR1
  • Int'l Joint Research
• [Presentation] Invariant NKT cells recognize leukemia cells in a CD1d independent manner (2019)
  • Author(s): 青木 孝浩, 高見 真理子, 高谷 具純, 本吉 究, 石井 絢菜, 岡田 玲緒奈, 日野 もえ子, 下条 直樹, 本橋 新一郎
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] 膠芽腫に発現するCD1d分子はNKT細胞を用いた免疫療法における有望な標的となる (2019)
  • Author(s): 原 彩佳, 那須 亮, 高見 真理子, 廣野 誠一郎, 松谷 智郎, 中山 俊憲, 岩立 康男, 本橋 新一郎
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Reduced RasGRP1 expression supports survival of regulatory T cells under continuous TCR stimulation (2018)
  • Author(s): Takami, M., Cunha, C., Iwashima, M.
  • Organizer: Cold Spring Harbor meeting on Gene Expression & Signaling in the Immune System
  • Int'l Joint Research
• [Presentation] Phase II study of α-Galactosylceramide-pulsed antigen presenting cells for advanced or recurrent non-small cell lung cancer (2018)
  • Author(s): Motohashi, S., Kamata, T., Toyoda, T., Tanaka, T., Ihara, F., Takami, M., Yosino, I., Nakayama, T.
  • Organizer: 第47回日本免疫学会学術集会