Immunological Mechanisms of Synergistic Anti-cancer Activities by Activation of TLR9 and STING

2019 Fiscal Year Research-status Report

• Project/Area Number: 19K16833
• Research Institution: The University of Tokyo
• Principal Investigator: TEMIZOZ BURCU 東京大学, 医科学研究所, 助教 (30831862)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: synergy / TLR9 / STING / anti-tumor / cancer immunotherapy

Outline of Annual Research Achievements

TLR9 and STING agonists possess therapeutic potential both for cancer and infectious diseases by acting as anti-tumor agents and vaccine adjuvants.Yet, their therapeutic applications are limited as currently available TLR9 agonist is a weak IFN inducer and STING agonists rather induce type 2 immune responses.Therefore,by taking advantage of combinatorial use of TLR9 and STING agonists, we previously showed that TLR9 and STING agonists synergistically induce innate and adaptive IFNγ to become a robust type 1 adjuvant and anti-tumor agent in murine tumor models of melanoma and thymoma.Here, by focusing on Th1-inducing cytokine IL-12 and a clinically relevant pancreatic cancer model, molecular and immunological mechanisms of action of TLR9 and STING agonist combinations is being investigated.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Currently, cell lines expressing several parts of IL-12p40 promoter have been established and synergistic effect of TLR9 and STING agonists on IL-12p40 promoter activation is being tested in these cells. Also, anti-tumor effect of TLR9 and STING agonist combinations are being tested in several mice lacking innate/adaptive immunity-related genes by using peritoneal dissemination model of pancreatic cancer.

Strategy for Future Research Activity

Next, involvement of different immune cell types in the anti-tumor effect of TLR9 and STING agonist combinations will be evaluated by in vivo cell depletion, transfer or more knockout mice studies in pancreatic cancer model.

Research Products

• [Presentation] DMXAA derivatives as potential immunotherapeutics for autoinflammation (2020)
  • Author(s): Temizoz B.
  • Organizer: Young Investigators Symposium at The Institute of Medical Science The University of Tokyo (IMSUT), Tokyo, Japan
  • Invited
• [Presentation] Combination and inducible adjuvants targeting nucleic acid sensors (2019)
  • Author(s): Temizoz B.
  • Organizer: Gakuyukai Seminar at The Institute of Medical Science The University of Tokyo (IMSUT), Tokyo, Japan
  • Invited
• [Presentation] Immunological mechanism of synergistic anti-cancer activities by activation of TLR9 and STING (2019)
  • Author(s): Temizoz, B., Hioki, K., Takayuki, S., Kobari, S., Jounai, N., Kusakabe, Lee, MSJ., T., Coban, C., Kuroda, E., and Ishii, K. J
  • Organizer: 13th Vaccine Congress, Bangkok, Thailand
  • Int'l Joint Research
• [Presentation] Immunological mechanism of synergistic anti-cancer activities by activation of TLR9 and STING (2019)
  • Author(s): Temizoz, B., Hioki, K., Takayuki, S., Kobari, S., Jounai, N., Kusakabe, Lee, MSJ., T., Coban, C., Kuroda, E., and Ishii, K. J.
  • Organizer: 48th Annual Meeting of the Japanese Society of Immunology (JSI), Hamamatsu, Japan
  • Int'l Joint Research