Development of iNKT cell-based immunotherapy targeting neuroblastoma by canceling the immunosuppression in the tumor microenvironment

• Project/Area Number: 18K16274
• 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: Chiba University
• Principal Investigator: Harada Kazuaki 千葉大学, 医学部附属病院, 医員 (00748767)
• 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: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 樹状細胞 / NKT細胞 / 神経芽腫 / 腫瘍免疫 / 免疫抑制

Outline of Final Research Achievements

We sought to determine the mechanism by which neuroblastoma inhibits antitumor immunity. When the culture supernatants from neuroblastoma cell lines (NLF, GOTO) were added monocyte derived dendritic cell (moDC) culture, cells retained CD14 with lower CD1a expression and produced much less IL-12 compared to control moDCs. Furthermore, IFN-γ production was reduced by iNKT cells stimulated with dendritic cells induced by the addition of culture supernatants from neuroblastoma cell lines.
These results suggested that immunosuppression via dendritic cell dysfunction may also exist in the tumor microenvironment in neuroblastoma.

Academic Significance and Societal Importance of the Research Achievements

がん細胞によって産生される免疫抑制性可溶性因子によって、免疫寛容誘導性樹状細胞(tolerogenic DC)が腫瘍微小環境で誘導されることが、複数のがん種において報告されている。本研究により、神経芽腫細胞株の培養上清に含まれる可溶性因子が、tolerogenic DCを誘導し、NKT細胞活性化能を低下させることが示され、神経芽腫による抗腫瘍免疫に対する免疫抑制機序の一端を明らかにした。

Research Products

• [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
• [Presentation] 神経芽腫細胞由来の液性因子による樹状細胞への抑制効果に関する研究 (2019)
  • Author(s): 原田和明
  • Organizer: 第56回日本小児外科学会学術集会
• [Presentation] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): 原田和明
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): 吉澤比呂子
  • Organizer: EMBO workshop, CD1-MR1: Beyond MHC-restricted lymphocytes
  • Int'l Joint Research