2020 Fiscal Year Final Research Report
Immunological Mechanisms of Synergistic Anti-cancer Activities by Activation of TLR9 and STING
Project/Area Number |
19K16833
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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Research Institution | The University of Tokyo |
Principal Investigator |
TEMIZOZ BURCU 東京大学, 医科学研究所, 助教 (30831862)
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Project Period (FY) |
2019-04-01 – 2021-03-31
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Keywords | TLR9 / STING / Synergy / Antitumor / Combination / IL-12 |
Outline of Final Research Achievements |
TLR9 and STING agonists offer therapeutic applications both as antitumor agents and vaccine adjuvants. Yet, clinically available TLR9 agonist is a weak IFN inducer and STING agonists induce undesired type 2 immunity, restricting their clinical applications. We previously showed that TLR9 and STING agonists synergized for induction of innate and adaptive IFNγ and became an advantageous type 1 adjuvant and robust antitumor agent. Here,we further show that local combination treatment promoted strong long term antitumor immunity in pancreatic cancer model via the mechanisms involving cooperative action of IL-12 and type I IFNs. Mechanistically, combination synergistically induce IL-12 and type I IFNs in APCs. By focusing on the Th1-inducing cytokine IL-12, we found that synergistic effect of the combination on IL-12p40 is transcriptionally regulated and observed on protein,mRNA and promoter activation levels. Thus,our combination may offer therapeutic applications as a potent Th1-inducer.
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Free Research Field |
Cancer immunotherapy
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Academic Significance and Societal Importance of the Research Achievements |
Identifying the mechanisms mediating synergistic as well as anti-tumor effect of combination of TLR9 and STING agonists is important. Because this may aid in development of novel treatment strategies based on combinatorial use of such adjuvants for cancer immunotherapy.
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