Effect of AhR signaling in iNKT cell based immunotherapy for lung cancer

• Project/Area Number: 16K19974
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• 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): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: NKT細胞 / 免疫療法 / AhRシグナル / 肺癌 / 免疫学 / 免疫治療

Outline of Final Research Achievements

To improve our current iNKT cell based immunotherapy for lung cancer, I focused on aryl hydrocarbon receptor (AhR) signaling. I hypothesized that AhR signaling suppresses an immune checkpoint molecule, PD-L1/PD-L2 expression on iNKT cells, thus augmenting anti-tumor effect of iNKT cells.
PD-L1 expression on iNKT cells was downregulated in the presence of AhR ligand. These data suggest that AhR signaling negatively regulates PD-L1 expression. However, AhR signaling did not affect anti-tumor effect of iNKT cells. When monocytes derived DCs (moDCs) were cultured in the presence of AhR agonist, moDCs downregulated PD-L1/PD-L2 expression. Moreover, AhR agonist-treated moDCs induced enhanced cytokine production of iNKT cells. These data indicate that AhR agonist enhances moDC function to induce greater cytokine production by iNKT cells. AhR agonist treatment could be combined with our current iNKT cell based immunotherapy as next generation of combination therapy.

Research Products

• [Journal Article] Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with or without malignant solid tumors. (2018)
  • Author(s): Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, and Motohashi S
  • Journal Title: Pediatr. Surg. Int. Volume: 34 Issue: 2 Pages: 169-176
  • DOI: 10.1007/s00383-017-4185-1
  • Peer Reviewed
• [Journal Article] Invariant natural killer T infiltration in neuroblastoma with favorable outcome. (2018)
  • Author(s): Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, and Motohashi S
  • Journal Title: Pediatr. Surg. Int. Volume: 34 Issue: 2 Pages: 195-201
  • DOI: 10.1007/s00383-017-4189-x
  • Peer Reviewed
• [Journal Article] Blockade of Programmed Death-1/Programmed Death Ligand pathway enhances the antitumor immunity of human invariant Natural Killer T cells. (2016)
  • Author(s): Kamata T, Suzuki A, Mise N, Ihara F, Takami T, Makita Y, Horinaka A, Harada K, Kunii K, Yoshida S, Yoshino I, Nakayama T, and Motohashi S.
  • Journal Title: Cancer Immunol Immunother. Volume: 65 Issue: 12 Pages: 1477-1489
  • DOI: 10.1007/s00262-016-1901-y
  • Peer Reviewed / Open Access
• [Presentation] NKT細胞のがん免疫療法における役割と今後の展望 (2017)
  • Author(s): 本橋 新一郎、高見 真理子
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] A role of AhR signaling in NKT cell immunotherapy. (2017)
  • Author(s): Takami, M., Ihara, F., Kamata, T., Motohashi, S.
  • Organizer: CD1-MR1 2017
  • Int'l Joint Research
• [Presentation] Regulatory T cells increased in advanced head and neck cancer patients suppress NKT cell function and correlate with disease progression. (2017)
  • Author(s): Ihara, F., Sakura, D., Takami, M., Okamoto, Y., Motohashi, S.
  • Organizer: CD1-MR1 2017
  • Int'l Joint Research
• [Presentation] AhR signaling enhances moDC function to activate NKT cells. (2017)
  • Author(s): Takami, M., Ihara, F., Kamata, T., Motohashi, S.
  • Organizer: 第46回日本免疫学会学術集会