2020 Fiscal Year Annual Research Report
Immunological Mechanisms of Synergistic Anti-cancer Activities by Activation of TLR9 and STING
Project/Area Number |
19K16833
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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 | STING / TLR9 / synergy / anti-tumor immunity / c-di-AMP / K3 CpG |
Outline of Annual Research Achievements |
TLR9 and STING agonists offer therapeutic applications both as anti-tumor 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. Our previous study, taking the advantage of combinatorial use of these adjuvants, showed that TLR9 and STING agonists synergized for induction of innate and adaptive IFNγ and became an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a monotherapeutic agent for cancer immunotherapy. Here, we show that combination of TLR9 and STING agonists synergistically induce IL-12 and type I IFN production from murine APCs. In particular, synergistic effect of the TLR9 and STING agonists on IL-12p40 are observed on protein, mRNA and promoter activation levels and transcriptional regulation is mediated by a 200 bp region situated at 983 bp upstream of IL-12p40 transcription initiation site. Moreover, local combination treatment promoted strong anti-tumor immunity in Pan02 peritoneal dissemination model via the mechanisms involving both CD4 and CD8 T cells, as well as co-operative action of IL-12 and type I IFNs. Furthermore, rechallenge studies in the long term survivors suggested the elicitation of Pan02-specific memory responses that provide protection against secondary tumor challenge. Therefore, combination of TLR9 and STING agonists may have clinical applications as potent anti-tumor agents.
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Research Products
(1 results)